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Principles of chemotherapy and radiotherapy
REVIEW
Principles of chemotherapy and radiotherapy
The doxorubicin is delivered in a liposome microscopic vesicle that penetrates the abnormal tumour vasculature and then releases the drug into that tissue. Gemcitabine - an antimetabolite that works as a nucleoside analogue replacing cytidine during DNA replication resulting in apoptosis. The majority of side effects of treatment are caused by the effect of the drugs on the cells of the normal tissues as they divide. Side effects can be acute - occurring during treatment, or late - occurring months to years later. The greatest impact of chemotherapy is seen in those normal cells that have a high cell turnover such as hair follicles, mucosal lining cells of the GI tract and the bone marrow. The normal cells are usually able to repair the damage in between doses of treatment minimising the risks of long-term damage. The different chemotherapy agents cause differing side effects, and each individual patient will experience the side effects to different degrees. Table 1 lists the potential side effects of chemotherapy. Candidates for chemotherapy should be fit enough to tolerate the effects of chemotherapy. Ideally they need to be WHO performance status 0e2 (Box 2) with adequate renal, hepatic and haematological function. Treatment delivered to individuals outside these specifications can lead to increased morbidity or mortality. The only exception to this is for patients who present a new diagnosis of an advanced rapidly progressing chemosensitive cancer. In these situations treating a patient who has a poor performance status with a less toxic chemotherapy agent, such as carboplatin, may paradoxically result in symptomatic relief and physical improvement in their PS. The decision to administer chemotherapy to any patient is highly individualised and should be made by an experienced oncologist. Intravenous (IV) chemotherapy treatment is delivered in cycles. The duration of the cycle varies according to the drug combination used. Standard carboplatin and paclitaxel is delivered on day 1 of a 21 day cycle. Administering treatment in this cyclical pattern enables time for the normal cells to recover prior to the next cycle, and in addition allows the cancer cells to progress through the cell cycle to a more vulnerable phase and therefore improve cell kill rates.
Sarah Smith Sarah Prewett
Abstract The current management of all gynaecological malignancy requires complex multidisciplinary investigation and discussion, leading to multi-modality treatment. The delivery of systemic therapy or radiotherapy can have different aims depending on the type of cancer, clinical context and patient wishes. This review explores the systemic treatment options and radiotherapy that form part of the standard management of this group of tumours and looks at current research that may help shape the treatment of the future.
Keywords cancer; cervix; chemotherapy; endometrium; ovary; radiotherapy
Systemic therapy Systemic therapy refers to drug treatments that travel through the bloodstream to reach cancer cells throughout the body. These agents include chemotherapy, targeted agents and endocrine therapy. Systemic therapies can be used as a curative treatment, often as part of a multi-modality approach, or as a palliative treatment to help control the disease and symptoms for as long as possible. Box 1 summarises the aims of treatment.
Chemotherapy Malignant tumours are characterised by rapid, uncontrolled cell division. The therapeutic effects of chemotherapy are produced by interrupting cell division, leading to cell death. Some chemotherapy agents can only affect cells that are dividing and are termed cell cycle specific. Others affect cells in any phase including the rest phase and are termed cell cycle non-specific (Figure 1). The commonly used chemotherapy agents in gynaecological malignancy include the following: Carboplatin and cisplatin e these are Platinum agents that form intra and inter strand DNA cross links inhibiting DNA synthesis and cell replication leading to apoptosis. Paclitaxel - a taxane that stabilises microtubules causing mitotic halt, leading to cell death. Liposomal Doxorubicin - an anthracycline that binds DNA and inhibits nucleic acid synthesis leading to cell death.
Dose Dense Chemotherapy: Dose Dense Chemotherapy refers to a regime that delivers treatment more frequently than every 3 weeks. It is usually associated with greater toxicity. Its use in ovarian cancer is currently being assessed in clinical trials, with a regime that involves giving Carboplatin every 3 weeks with paclitaxel given weekly. To date studies have shown some benefits in progression free survival and overall survival, mainly in patients after surgical treatment where there is over 1 cm of residual disease after surgery. Patients with clear cell or mucinous carcinomas or those receiving bevacizumab have not been shown to benefit from dose dense treatment, although further results are awaited. In the UK the ICON8 and ICON8b studies are evaluating dose dense treatments with and without bevacizumab. Dose dense treatment is not part of UK standard practice outside trials in first line treatment at present.
Sarah Smith MBBS BMedSci MRCP FRCR is a Consultant Clinical Oncologist at Cambridge University Hospitals NHS Foundation Trust and Bedford Hospital NHS Trust, UK. Conflicts of interest: none.
Intraperitoneal chemotherapy in ovarian cancer: intraperitoneal chemotherapy (IP) is a subject of investigation internationally, but is not currently part of UK standard practice for
Sarah Prewett MBBCh MSc FRCR is a Consultant Clinical Oncologist at Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Conflicts of interest: none.
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REVIEW
demonstrates that lesions smaller than 3 mm have significantly higher drug exposure from IP administration compared with IV administration. Studies have looked at treating women with optimally debulked disease (no residual or less than 1 cm of residual disease) who had not received neoadjuvant treatment with a combination of IV and IP chemotherapy. The most commonly used IV/IP regimen comes from GOG 172 and combines intravenous paclitaxel day 1, intraperitoneal cisplatin day 2, intraperitoneal paclitaxel day 8 repeated six times. The main meta-analysis showed that compared to IV treatment alone, the IV/IP regimen resulted in a reduced risk of death and better disease free survival, although higher toxicity was seen. There are limitations to the meta-analysis as the IV treatment delivered differed between the studies and may have influenced outcome. A large trial of IP chemotherapy in the setting of interval cytoreductive surgery after 3 cycles of neoadjuvant chemotherapy, has shown an increase in progression free survival when compared to surgery along. IP chemotherapy is delivered through an implanted port placed at the time of surgery or at a later date. The patient is
Treatment Aims Radical e Treatment delivered without surgery with the aim of cure Neo-adjuvant e Treatment delivered before surgery to maximise the chance of a complete resection and cure Adjuvant e Treatment delivered after surgery to reduce the risk of cancer relapse and increase cure rate Palliative e Treatment delivered to control the cancer or symptoms from cancer when cure is not possible. Box 1
ovarian cancer as there is no consensus on whether IP therapy should be given as part of standard treatment for women with optimally de-bulked ovarian cancer. Compared with intravenous treatment, intraperitoneal administration permits a significantly higher drug concentration to be delivered within the abdominal cavity. Analysis of intra-tumoral drug concentrations
Figure 1 The cell cycle. G0: rest phase. The cell is outside the cell cycle and not dividing; G1 phase: rapid growth and metabolic activity, mRNA and protein synthesis; S phase: growth and DNA replication; G2 phase: growth, protein synthesis and final preparation for division; M phase: Prophase e chromatin, condenses into chromosomes, Metaphase e chromosomes attach to the spindle fibres, Anaphase e chromosomes move to opposite poles of the spindles, Telophase e two nuclei are formed, Cytokinesis e the cell cytoplasm splits into two forming two cells.
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REVIEW
or because NICE have not ruled them to be cost effective. The Cancer Drugs Fund was set up to improve access to cancer drugs for patients in England and this fund allows patients to access some of these drugs on a case by case basis. Targeted agents can be divided into two categories: Monoclonal Antibodies - which target specific antigens on the cell surface such as the anti-angiogenic antibody bevacizumab Small Molecules - which penetrate the cell membrane to act on intracellular targets such as the PARP inhibitors
Potential side effects of chemotherapy Gastrointestinal tract nausea, vomiting, mucositis, stomatitis, gastritis, diarrhoea, constipation, colitis Haematological anaemia, thrombocytopenia, neutropenia, thromboembolic events Neurological memory impairment, peripheral neuropathy, ototoxicity, headache Hepatic and renal elevation of LFTs, renal dysfunction, renal failure Cardiovascular Hypo or hypertension, bradycardia, arrhythmia Musculoskeletal arthralgia, myalgia, asthenia General effects alopecia, fatigue, hypersensitivity, dental problems, onycholysis, early menopause, infertility, low electrolytes, rash
moved from side to side every 15 min for 1 hour to help disperse the chemotherapy. The main complications include higher neurotoxicity compared with IV treatment, nephrotoxicity, abdominal pain, peritonitis, bowel obstruction, bowel necrosis and perforation. Additionally IP chemotherapy can only be provided in centres with the appropriate infra-structure, equipment and trained professionals, and therefore the implementation may be challenging if future studies do show superior outcomes for treatment of ovarian cancer.
Monoclonal antibodies: bevacizumab is a humanised monoclonal antibody targeting the VEGF ligand, and therefore inhibits angiogenesis. It is licensed in the treatment of gynaecological malignancy in the following situations: - First line treatment of advanced (stage 3 or 4) ovarian cancer in combination with carboplatin and paclitaxel - First platinum-sensitive relapse of ovarian cancer in combination with carboplatin and gemcitabine or, - Platinum-resistant ovarian cancer in combination with paclitaxel or liposomal doxorubicin or topotecan - Persistent, recurrent or metastatic cervix cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan In the UK at present, bevacizumab is not available on the NHS unless an individual application is made to the Cancer Drug Fund. The fund will give approval for first line treatment of advanced ovarian cancer based on the GOG 218 study that showed a progression free survival advantage of 14 months compared to 10 months with bevacizumab given during chemotherapy then as a single agent to 1 year. No overall survival advantage was found. The fund will also approve its use in the first line treatment of recurrent or metastatic cervical cancer, based on the GOG 240 study that showed a significantly improved overall survival of 17 vs 13.3 months when bevacizumab was given with platinum based chemotherapy. The side effects of bevacizumab include GI perforation (0.9%), haemorrhage (24%), severe hypertension (18%), nephrotic syndrome (7%), infusion reactions (3%), fistula (2%), thromboembolic events (2.6%) and non-healing wounds. Therefore it requires judicious use in women with potential serosal involvement of the bowel, and must not be used within 4 weeks of planned surgical treatment.
Targeted therapy Targeted drugs are a newer form of systemic treatment and are increasingly used for treatment of malignancy. These act on specific molecular targets involved in the growth or spread of cancer cells. As these targets are not found in high concentrations in normal cells the side effects are potentially fewer when compared to chemotherapy. When newer cancer drugs are licensed they first need to be approved by the relevant independent organisations before the NHS can routinely prescribe them. In England this is the National Institute for Health and Care Excellence (NICE). Arrangements are different in Wales and Northern Ireland but they often follow NICE guidance. Scotland has its own arrangements and uses the Scottish Medicines Consortium. Some drugs are not recommended by NICE, either because they have not yet been assessed,
Poly ADP ribose polymerase (PARP) Inhibitors: patients with BRCA 1 or 2 mutations have cancers with increased reliance on PARP (a cellular protein) to repair DNA. When a cell fails to repair the damaged DNA it dies. These patients show high response rates to PARP inhibitors such as olaparib or rucaparib. The SOLO1 phase III clinical trial investigated the effects of maintenance olaparib in patients with advanced ovarian cancer carrying the BRCA mutation. This trial showed that following first line platinum based treatment, addition of the oral PARP inhibitor olaparib for 2 years significantly improved 3 year disease free progression from 27% on placebo to 60%. Olaparib given in this context is now available in the UK via the cancer drug fund. The phase II clinical trial Study 191 evaluated the use of olaparib in patients with platinum-sensitive recurrent ovarian
Table 1
WHO Performance Status 1 Able to carry out all activity without restriction 2 Restricted strenuous activity but ambulatory and able to carry out light work 3 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours 4 Symptomatic and in a chair or bed for more than 50% of the day but not bedridden 5 Completely disabled. Unable to carry out any self care. Totally confined to bed or chair Box 2
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REVIEW
sensitising the tumour cells to the effects of radiation and increasing tumour cell death rates.
cancer. This study showed that olaparib extended progression free survival from 4.3 to 11.2 months when compared with surveillance alone in BRCA mutated patients. Smaller benefits were seen in the BRCA wild type (non-mutated) patients. In the UK, NICE has approved olaparib in BRCA mutated patients with platinum sensitive disease after chemotherapy in a maintenance role in keeping with its license. Niraparib is another PARP inhibitor that is available for platinum sensitive recurrent ovarian high grade serous carcinoma after second line or later treatment in patients who have a partial or complete response to platinum based chemotherapy provided they have not had a PARP inhibitor before. It is available for both BRCA mutated and wild type patients, based on the NOVA study which showed an increased progression free survival in both groups, although the responses were more significant in the BRCA mutated group. PARP inhibitor side effects are usually mild to moderate and include fatigue (63%), nausea (77%), diarrhoea (34%), and anaemia (39%).
The planning process Prior to starting radiotherapy, most patients have a planning CT scan which is used to aid in the planning of their individualised treatments. The clinical oncologist or radiotherapy planner will evaluate the CT images alongside any diagnostic imaging, clinical pictures, and endoscopy reports, and then combine all the information to define the target area. The first step in planning is to define or delineate any visible tumour seen on imaging, and this is termed gross tumour volume (GTV). PET-CT and MRI scans can be fused with the planning CT scan to help define these target volumes. Next an additional margin is usually added around the gross visible tumour to account for microscopic spread and also expanded to include other areas at risk of disease. It is vital to be aware of the likely biological behaviour of the tumour and typical patterns of nodal spread, so that all ‘at risk’ areas may be included if needed. This volume is the clinical target volume (CTV), and it is possible to treat different CTV volumes with different doses, dependent upon their risk. A further margin is then added to give the final volume for planning and this is called the planning target volume (PTV). This margin accounts for daily changes in patient positioning during a typical course of treatment, and factors in alterations in the bladder and bowel filling for example, which can lead to variations in the position of pelvic organs each day (Figure 2). Within the pelvis, there are a number of organs which can be adversely affected by radiation and cause both acute (during treatment) and late toxicities (months or years later). These are termed organs at risk (OARs) and include the bladder, bowel, vagina and femoral heads. The radiation dose to these sensitive structures is minimised if possible, to reduce potential side effects, but it is likely that these structures will inevitably receive some radiation exposure. There is a risk of causing significant long-term side effects to the bladder and bowel in up to 15e20% of patients receiving a curative radiation dose for cervical cancers, but the risk of this side effect has to be weighed up against the risk and consequences of uncontrolled disease or recurrence. Long term late effects may also include stenosis of the vagina, bone pain, haematuria, early menopause/infertility and rectal bleeding.
Endocrine Therapy: endocrine or hormonal therapy aims to reduce the influence of oestrogen on cancer cell growth. Treatment is usually administered as oral tablets every day. They are usually a well-tolerated group of drugs, without the significant toxicities often associated with chemotherapy treatment. Tamoxifen is a selective oestrogen receptor modulator that competitively inhibits oestrogen binding to the oestrogen receptor. It has mixed antagonist and agonist activity depending on the target tissue. Letrozole is a non-steroidal aromatase inhibitor that blocks conversion of androgens into oestrogens in peripheral tissues. Megesterol acetate and medroxyprogesterone acetate are synthetic progestins. Their anti-cancer action is not completely understood. Possibilities include an effect at the pituitary level, reducing gonadotrophin production and therefore oestrogen production, and also local tissue effects at the oestrogen/progesterone receptors. For women with asymptomatic relapsed epithelial ovarian cancer, endocrine therapy may provide therapeutic benefit. Studies have shown that Letrozole has response rates of 9%, with stable disease in 42%. Tamoxifen has response rates of 10% with stable disease in 32% of patients. In women with relapsed endometrial cancer megestrol acetate, medroxyprogesterone acetate and tamoxifen have demonstrated activity in studies with reported response rates of up to 15e30%, predominantly in lower grade tumours.
Radiotherapy delivery Many centres in the UK deliver radiotherapy treatments via a plan made up of 3 or 4 treatment beams, delivered in an anteroposterior (AP) and right and left lateral beam arrangement. This leads to the highest dose being achieved in the middle of the patient in the region of a central tumour, but also can result in significant doses being deposited outside of the tumour, in the surrounding normal tissues such as the skin or bowel. The development of intensity-modulated radiotherapy (IMRT) has helped improve the coverage of deep-seated tumours in the pelvis by improving the dose-homogeneity and reducing high or low dose areas and allowing sharper dose-gradients to form at the tumour or target volume edges. This reduces the unwanted doses to the normal tissues outside of the target, and reduces the normal tissue toxicity effects. IMRT achieves this by increasing
Radiotherapy Radiotherapy utilises high energy x-rays which are generated by machines called linear accelerators (LINACs). Each treatment is known as a fraction. Fractions are usually delivered daily for five days (Monday to Friday) repeatedly over a course of a few weeks. This is typically 5 weeks for patients with gynaecological cancers receiving radical or adjuvant treatment. Sometimes chemotherapy is given concurrently with the radiotherapy (known as chemo-radiation), with the purpose of
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REVIEW
Repair - The above principle is known as repair. Fractionating the radiotherapy treatment allows time for sub-lethal damage to normal tissue cells to be repaired. Tumour cells are often unable to recover due to defects in their repair pathways. Re-oxygenation - Hypoxic cells are more resistant to the indirect effect of radiation, and this is the rationale for blood transfusions to maintain haemoglobin levels and therefore improve oxygen levels within the tumour. Redistribution e This refers to the effect that a fractionated radiation schedule has upon the timing of the tumour cell cycle, with multiple fractions more likely to catch the cells in a more sensitive part of the cycle. Figure 2 Radiotherapy planning CT scan showing volumes defined during planning process e GTV, CTV and final target volume e PTV.
Repopulation - Tumour cells can start to re-grow rapidly after around 4 weeks and therefore increasing the length between treatments may compound this effect and paradoxically increase tumour growth. Understanding repopulation underpins the need to complete a course of radiotherapy on time, with no delays, and the importance of not stopping treatment or missing fractions. Most radiotherapy fractions are delivered within 10e15 min but some of the newer techniques can take a little longer, for example if image-guidance is used (IGRT). This involves pretreatment imaging to ensure that the area being treated matches what was originally intended on the planning scan. These techniques may involve the matching of bony anatomy between the two scans and small moves can be made to the position of the patient to correct for any discrepancy prior to daily treatment. Patients receiving radical radiotherapy for cervical cancer may have variations in the amount of faeces and air present in the rectum each day, and bladder capacity often reduces during 5 weeks of treatment due to the effects of radiotherapy. This can affect the position of the cervix or target volume and potentially lead to a geographical miss unless not corrected for. This is where the role of image-guided radiotherapy can be vital in ensuring a radical dose is actually delivered to the tumour itself, and is increasingly important where higher ‘boost’ doses are delivered.
the number of radiation beams used to treat the tumour, sometimes using multiple mini beam-lets to enable this. One drawback to this modern technique is that a greater volume of normal tissue may be exposed to a lower dose than before, termed the low -dose bath effect, and this may contribute to a higher risk of second cancers in later life. This is a real issue for young patients receiving radical radiation courses, and second malignancies within a previous radiation field can be difficult to treat. Figure 3 shows an example of the dose distribution seen in a patient treated with IMRT. Mechanism of action of radiotherapy Radiotherapy aims to cause irreversible damage to the cell DNA by breaking the strands of the DNA helix which cannot be repaired, and therefore triggering the cell to apoptose when it attempts to replicate during mitosis. Double stranded DNA helix breaks are more likely to result in cell death than single strand breaks, because a remaining single DNA strand can act as a template for replication if it remains intact. There are five radio-biological principles known as the five R’s that account for how we deliver radiotherapy in practice, and how radiation influences tumour cells. The five Rs include e repair, re-oxygenation, re-distribution, radiosensitivity and re-population.
Brachytherapy The process of brachytherapy involves placing an internal applicator within a body cavity to enable a radioactive source to travel through it to the area requiring treatment. This could be the cervix itself or the vaginal vault if a hysterectomy has taken place. In endometrial cancer, brachytherapy to the vaginal vault is sometimes offered post-operatively to reduce the risk of local recurrence at this site. This practice is based on the PORTEC-2 trial showing a reduction in local recurrence and is typically offered to intermediate-risk endometrial cancers. No improvement in overall survival has been shown. Higher risk patients may be offered pelvic radiation to reduce pelvic recurrence risk. Current UK management of gynaecological cancers Ovarian, Tubal and Primary Peritoneal Tumours: early ovarian or tubal cancer (stage I and II) accounts for about 20% of all cases. Upfront surgery is the main treatment. Adjuvant
Figure 3 Intensity modulated radiotherapy of post-operative cervical cancer patient with nodal involvement. Note the colourwash dose distribution (red ¼ hottest, blue ¼ coolest dose) and coverage of the PTV45 e target volume, and relative sparing of the femoral heads.
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REVIEW
treatment with chemotherapy is delivered to high risk patients such as those with stage IC or II disease of any grade, clear cell or high grade tumours at any stage. The evidence for adjuvant treatment comes from meta-analyses including the Cochrane Review published in 2009, which showed a survival advantage for those with high risk features, or residual disease after surgery. The standard treatment is 6 cycles of carboplatin chemotherapy either as a single agent or in combination with paclitaxel. There is a lack of robust data on the best regimen and the current NICE guidance recommends single agent carboplatin. Advanced Ovarian Cancer (stage III and IV) is treated with primary surgery if the disease can be optimally de-bulked at that time (often stage IIIa and b), followed by adjuvant carboplatin and paclitaxel chemotherapy. If it is considered that optimal surgery is not achievable or appropriate in the upfront setting (often in extensive stage IIIc or IV disease) then neo-adjuvant carboplatin and paclitaxel is given for 3 cycles followed by interval cytoreductive surgery, and then a further 3 cycles of carboplatin and paclitaxel. Bevacizumab may be considered in addition, which would then continue as a maintenance treatment to complete 1 year. The PARP inhibitor olaparib has recently been approved for use as first-line maintenance treatment for women platinumsensitive disease who have the BRCA mutation, following their first course of chemotherapy. This has been shown to delay the onset of relapse and even has the potential to cure the disease. Unfortunately the majority of late stage ovarian cancer patients experience recurrence. There is a role for surgery in a minority of highly selected patients. However the management of relapse in most cases tends to be chemotherapy-based with the aim of treatment being disease and symptom control. If the patient has platinum-sensitive relapse (more than 6 months since previous platinum based treatment) then a combination of carboplatin with liposomal doxorubicin or gemcitabine can be used. If platinum-resistant (less than 6 months since the last platinum treatment) then liposomal doxorubicin or weekly paclitaxel are frequent choices of agent. Treatment is then delivered in an intermittent basis for as long as possible at times when the disease is rapidly progressing on CT or causing symptoms, aiming to preserve quality of life in addition to extending life. Hormonal treatments can also be used in this setting. PARP inhibitors can also be used for selected women who have platinum-sensitive disease following two courses of chemotherapy, irrespective of BRCA status. At present in the UK the 5-year survival for ovarian cancer overall is 46%.
surgery can be considered depending upon the tumour characteristics together with age or patient wishes, when a radical trachelectomy can be considered. Adjuvant chemo-radiotherapy is recommended for high risk patients with risk factors for recurrence. These include positive resection margin, unexpected lymph node involvement or parametrial invasion. There is a survival benefit with the addition of adjuvant chemo-radiation in this population. For those with intermediate risk factors such as tumour >4 cm, close vaginal margins, deep stromal invasion or the presence of lymphovascular space invasion (LVSI), (chemo-) radiation may also be considered to reduce the risk of pelvic recurrence. For the more advanced stage tumours >IB2, or in the presence of lymph node involvement then the standard of care is primary chemo-radiation. This can achieve high rates of local control even with stage IVA disease. In the UK, a typical treatment regime would be to deliver external beam radiotherapy (EBRT) at a dose of 45 Gy in 25 fractions across 5 weeks. The target volume would include the cervix, parametria, uterus and the pelvic nodes (and possibly PA nodes) at risk. IMRT techniques are increasingly used to deliver treatment, aiming to minimising radiation dose to the organs at risk, and in particular the bladder and bowel. Weekly cisplatin chemotherapy is given simultaneously as an intravenous infusion during the 5 week treatment regime, and is usually well tolerated although it does increase the risk of nausea and vomiting. The dose of radiation required to adequately treat cervical cancer is greater than that which can be delivered safely using external beam techniques alone, due to the radiation-sensitivity of the other pelvic structures. Patients on a radical treatment pathway therefore go on to receive brachytherapy immediately after their initial external beam treatment. This enables a tumoricidal dose to be achieved at the tumour/cervix, and it can be delivered with an acceptable level of normal tissue damage. Brachytherapy involves placement of applicators directly into the cervix/uterus to enable a radioactive source to be positioned within the applications, and therefore deliver a high radiation dose to the target. This can be carried out in a number of ways, and in our centre involves an inpatient admission with 3 or 4 fractions delivered over a number of days. The radiation delivery planning process involves a team of specialist physicists, radiographers and clinical oncologists and can be complex and often requires both MRI and CT imaging. Palliative courses of radiotherapy to control local disease, usually without chemotherapy, can be offered to patients who have metastatic disease, or who are not fit enough for radical treatment. Controlling pelvic disease with radiotherapy even in metastatic disease may still be recommended, as poorly controlled pelvic disease can be unpleasant and difficult to manage. For metastatic cervix cancer, palliative chemotherapy may also be considered. Platinum based combination chemotherapy is recommended. The addition of bevacizumab adds a small survival benefit.
Cervical tumours: planning treatment for cervical cancer requires accurate clinical staging of cervical tumours, and examination under anaesthesia (EUA) often forms part of the clinical staging, except in the earliest stages with small tumour. Early stage tumours beyond stage 1A1 and up to stage 1B1 (confined to the cervix and <4 cm) which are node negative, can be managed surgically and the standard operation would be a radical hysterectomy with or without bilateral salpingooophorectomy. Ovarian metastases are rare and the ovaries are usually conserved in younger patients. Pelvic lymphadenectomy is carried out to aid surgical staging and guide the need for postoperative adjuvant treatment. In selected cases fertility sparing
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Endometrial cancer The mainstay of endometrial cancer treatment remains surgery and usually involves a hysterectomy and bilateral salpingooophrectomy with or without regional lymph node staging.
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REVIEW
not possible. The radiotherapy dose would need to be at least 60 e65Gy, and if fit enough, chemotherapy with cisplatin would be given concurrently. The traditional approach would be to offer 45Gy to the pelvis over 5 weeks followed by a boost to the residual gross tumour. IMRT may be an alternative approach if available, and may allow delivery of a higher simultaneous boost dose to the primary tumour during delivery of pelvic radiotherapy.
Omental biopsy and biopsies of any suspicious pelvic or intraabdominal lesions may be appropriate in selected cases to aid in surgical staging. Patients with advanced disease may sometimes be offered cytoreductive surgery, even though surgery is unlikely to be curative (stages III-IVA), as there may be a survival benefit and palliation in those with minimal gross residual disease. In the presence of extra-pelvic metastatic disease, treatment is palliative and surgery may or may not be required depending upon the individual symptoms. In these circumstances chemotherapy may be appropriate for palliation only. Those with early stage disease (IA) without significant risk factors do not require adjuvant treatment, but those with intermediate or high risk factors should be considered for adjuvant radiotherapy and/or chemotherapy. Those with an intermediate risk of recurrence may benefit from adjuvant brachytherapy to the vaginal vault. This reduces local recurrence only at the vault and has no impact upon survival. Those with greater risk factors such as higher stages and or grade of tumour, and presence of LVSI may benefit from adjuvant pelvic radiotherapy to reduce the risk of a pelvic recurrence. Pelvic radiotherapy has not been shown to improve overall survival but comes with greater toxicity compared with brachytherapy alone. Adjuvant chemotherapy with carboplatin and paclitaxel in combination is frequently given prior to pelvic radiotherapy in those deemed to be at high risk of recurrence. The PORTEC 3 study showed that overall those that had chemotherapy in addition to radiotherapy had an improved 5 year overall survial of 5%. The greatest benefits were seen in those with stage 3 disease or serous histology. The same platinum doublet may be offered in metastatic disease to help palliate symptoms and typically 6 cycles may be delivered. For those with more indolent disease, lower grade tumours and those expressing oestrogen receptors (ER) or progesterone receptor (PR) positivity, hormonal therapy such as Megace may induce a response. A small percentage of patients may have a prolonged remission period. The Mirena IUS is sometimes used alone in patients with early stage, low grade disease who are unfit for treatment, or who still require fertility.
Vaginal tumours Vaginal tumours are rare. EUA is vital for planning purposes. Tumours within proximal (upper) two thirds of the vagina are usually treated in a similar manner as cervical tumours, often with radical chemo-radiation. Those in the distal third of the vagina are usually managed like vulval cancers. A FURTHER READING Tewari KS, Sill MW, Long 3rd HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014; 370: 734. NICE Clinical Guideline CG122: ovarian cancer: recognition and initial management, April 2011. Published. Reducing uncertainties about the effects of chemo radiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev, 2010 Jan 20; https://doi.org/10.1002/ 14651858.CD008285. CD008285. Tanner EJ, Leitao Jr MM, Garg K, et al. The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma. Gynecol Oncol 2011 Dec; 123: 548e52. Epub 2011 Sep. 25.
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Vulval tumours Vulval cancers are typically squamous cell carcinomas, and if caught early are best managed surgically. The operation entails a radical local excision or radical modified vulvectomy and the assessment of lymph node (LN) involvement is important prognostically. Those with stage IB disease or above and no palpable nodes require LN assessment either with sentinel node biopsy or node dissection. Positive margins should be re-excised where possible although radiotherapy can be an alternative to reduce risk of recurrence and should also be considered in cases with close margins, big tumours >4 cm and those with node positive disease. Primary chemo-radiation can be an option in patients unfit for surgery or in locally advanced disease where clear margins are
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Carboplatin in combination with paclitaxel is the most commonly used regimen in gynaecological malignancy. Candidates for chemotherapy should be of WHO performance status 0e2, with adequate renal, hepatic and haematological function. Treatment delivered to individuals outside these specifications can lead to increased morbidity or mortality. The developments of targeted agents are changing practice in the management of gynaecological tumours and have lower rates of toxicity compared to chemotherapy. Dose dense and intraperitoneal chemotherapy are not standard first line treatment options in the UK at present. Pelvic radiotherapy following a hysterectomy for endometrial cancer reduces the risk of local recurrence but does not impact on overall survival The standard radical treatment of cervical tumours greater than stage IB2, or with lymph node involvement is 5 weeks of radiotherapy with weekly cisplatin followed by brachytherapy to boost the tumour dose which may require an inpatient stay.
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Principles of chemotherapy and radiotherapy
The doxorubicin is delivered in a liposome microscopic vesicle that penetrates the abnormal tumour vasculature and then releases the drug into that tissue. Gemcitabine - an antimetabolite that works as a nucleoside analogue replacing cytidine during DNA replication resulting in apoptosis. The majority of side effects of treatment are caused by the effect of the drugs on the cells of the normal tissues as they divide. Side effects can be acute - occurring during treatment, or late - occurring months to years later. The greatest impact of chemotherapy is seen in those normal cells that have a high cell turnover such as hair follicles, mucosal lining cells of the GI tract and the bone marrow. The normal cells are usually able to repair the damage in between doses of treatment minimising the risks of long-term damage. The different chemotherapy agents cause differing side effects, and each individual patient will experience the side effects to different degrees. Table 1 lists the potential side effects of chemotherapy. Candidates for chemotherapy should be fit enough to tolerate the effects of chemotherapy. Ideally they need to be WHO performance status 0e2 (Box 2) with adequate renal, hepatic and haematological function. Treatment delivered to individuals outside these specifications can lead to increased morbidity or mortality. The only exception to this is for patients who present a new diagnosis of an advanced rapidly progressing chemosensitive cancer. In these situations treating a patient who has a poor performance status with a less toxic chemotherapy agent, such as carboplatin, may paradoxically result in symptomatic relief and physical improvement in their PS. The decision to administer chemotherapy to any patient is highly individualised and should be made by an experienced oncologist. Intravenous (IV) chemotherapy treatment is delivered in cycles. The duration of the cycle varies according to the drug combination used. Standard carboplatin and paclitaxel is delivered on day 1 of a 21 day cycle. Administering treatment in this cyclical pattern enables time for the normal cells to recover prior to the next cycle, and in addition allows the cancer cells to progress through the cell cycle to a more vulnerable phase and therefore improve cell kill rates.
Sarah Smith Sarah Prewett
Abstract The current management of all gynaecological malignancy requires complex multidisciplinary investigation and discussion, leading to multi-modality treatment. The delivery of systemic therapy or radiotherapy can have different aims depending on the type of cancer, clinical context and patient wishes. This review explores the systemic treatment options and radiotherapy that form part of the standard management of this group of tumours and looks at current research that may help shape the treatment of the future.
Keywords cancer; cervix; chemotherapy; endometrium; ovary; radiotherapy
Systemic therapy Systemic therapy refers to drug treatments that travel through the bloodstream to reach cancer cells throughout the body. These agents include chemotherapy, targeted agents and endocrine therapy. Systemic therapies can be used as a curative treatment, often as part of a multi-modality approach, or as a palliative treatment to help control the disease and symptoms for as long as possible. Box 1 summarises the aims of treatment.
Chemotherapy Malignant tumours are characterised by rapid, uncontrolled cell division. The therapeutic effects of chemotherapy are produced by interrupting cell division, leading to cell death. Some chemotherapy agents can only affect cells that are dividing and are termed cell cycle specific. Others affect cells in any phase including the rest phase and are termed cell cycle non-specific (Figure 1). The commonly used chemotherapy agents in gynaecological malignancy include the following: Carboplatin and cisplatin e these are Platinum agents that form intra and inter strand DNA cross links inhibiting DNA synthesis and cell replication leading to apoptosis. Paclitaxel - a taxane that stabilises microtubules causing mitotic halt, leading to cell death. Liposomal Doxorubicin - an anthracycline that binds DNA and inhibits nucleic acid synthesis leading to cell death.
Dose Dense Chemotherapy: Dose Dense Chemotherapy refers to a regime that delivers treatment more frequently than every 3 weeks. It is usually associated with greater toxicity. Its use in ovarian cancer is currently being assessed in clinical trials, with a regime that involves giving Carboplatin every 3 weeks with paclitaxel given weekly. To date studies have shown some benefits in progression free survival and overall survival, mainly in patients after surgical treatment where there is over 1 cm of residual disease after surgery. Patients with clear cell or mucinous carcinomas or those receiving bevacizumab have not been shown to benefit from dose dense treatment, although further results are awaited. In the UK the ICON8 and ICON8b studies are evaluating dose dense treatments with and without bevacizumab. Dose dense treatment is not part of UK standard practice outside trials in first line treatment at present.
Sarah Smith MBBS BMedSci MRCP FRCR is a Consultant Clinical Oncologist at Cambridge University Hospitals NHS Foundation Trust and Bedford Hospital NHS Trust, UK. Conflicts of interest: none.
Intraperitoneal chemotherapy in ovarian cancer: intraperitoneal chemotherapy (IP) is a subject of investigation internationally, but is not currently part of UK standard practice for
Sarah Prewett MBBCh MSc FRCR is a Consultant Clinical Oncologist at Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Conflicts of interest: none.
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demonstrates that lesions smaller than 3 mm have significantly higher drug exposure from IP administration compared with IV administration. Studies have looked at treating women with optimally debulked disease (no residual or less than 1 cm of residual disease) who had not received neoadjuvant treatment with a combination of IV and IP chemotherapy. The most commonly used IV/IP regimen comes from GOG 172 and combines intravenous paclitaxel day 1, intraperitoneal cisplatin day 2, intraperitoneal paclitaxel day 8 repeated six times. The main meta-analysis showed that compared to IV treatment alone, the IV/IP regimen resulted in a reduced risk of death and better disease free survival, although higher toxicity was seen. There are limitations to the meta-analysis as the IV treatment delivered differed between the studies and may have influenced outcome. A large trial of IP chemotherapy in the setting of interval cytoreductive surgery after 3 cycles of neoadjuvant chemotherapy, has shown an increase in progression free survival when compared to surgery along. IP chemotherapy is delivered through an implanted port placed at the time of surgery or at a later date. The patient is
Treatment Aims Radical e Treatment delivered without surgery with the aim of cure Neo-adjuvant e Treatment delivered before surgery to maximise the chance of a complete resection and cure Adjuvant e Treatment delivered after surgery to reduce the risk of cancer relapse and increase cure rate Palliative e Treatment delivered to control the cancer or symptoms from cancer when cure is not possible. Box 1
ovarian cancer as there is no consensus on whether IP therapy should be given as part of standard treatment for women with optimally de-bulked ovarian cancer. Compared with intravenous treatment, intraperitoneal administration permits a significantly higher drug concentration to be delivered within the abdominal cavity. Analysis of intra-tumoral drug concentrations
Figure 1 The cell cycle. G0: rest phase. The cell is outside the cell cycle and not dividing; G1 phase: rapid growth and metabolic activity, mRNA and protein synthesis; S phase: growth and DNA replication; G2 phase: growth, protein synthesis and final preparation for division; M phase: Prophase e chromatin, condenses into chromosomes, Metaphase e chromosomes attach to the spindle fibres, Anaphase e chromosomes move to opposite poles of the spindles, Telophase e two nuclei are formed, Cytokinesis e the cell cytoplasm splits into two forming two cells.
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or because NICE have not ruled them to be cost effective. The Cancer Drugs Fund was set up to improve access to cancer drugs for patients in England and this fund allows patients to access some of these drugs on a case by case basis. Targeted agents can be divided into two categories: Monoclonal Antibodies - which target specific antigens on the cell surface such as the anti-angiogenic antibody bevacizumab Small Molecules - which penetrate the cell membrane to act on intracellular targets such as the PARP inhibitors
Potential side effects of chemotherapy Gastrointestinal tract nausea, vomiting, mucositis, stomatitis, gastritis, diarrhoea, constipation, colitis Haematological anaemia, thrombocytopenia, neutropenia, thromboembolic events Neurological memory impairment, peripheral neuropathy, ototoxicity, headache Hepatic and renal elevation of LFTs, renal dysfunction, renal failure Cardiovascular Hypo or hypertension, bradycardia, arrhythmia Musculoskeletal arthralgia, myalgia, asthenia General effects alopecia, fatigue, hypersensitivity, dental problems, onycholysis, early menopause, infertility, low electrolytes, rash
moved from side to side every 15 min for 1 hour to help disperse the chemotherapy. The main complications include higher neurotoxicity compared with IV treatment, nephrotoxicity, abdominal pain, peritonitis, bowel obstruction, bowel necrosis and perforation. Additionally IP chemotherapy can only be provided in centres with the appropriate infra-structure, equipment and trained professionals, and therefore the implementation may be challenging if future studies do show superior outcomes for treatment of ovarian cancer.
Monoclonal antibodies: bevacizumab is a humanised monoclonal antibody targeting the VEGF ligand, and therefore inhibits angiogenesis. It is licensed in the treatment of gynaecological malignancy in the following situations: - First line treatment of advanced (stage 3 or 4) ovarian cancer in combination with carboplatin and paclitaxel - First platinum-sensitive relapse of ovarian cancer in combination with carboplatin and gemcitabine or, - Platinum-resistant ovarian cancer in combination with paclitaxel or liposomal doxorubicin or topotecan - Persistent, recurrent or metastatic cervix cancer in combination with paclitaxel and cisplatin or paclitaxel and topotecan In the UK at present, bevacizumab is not available on the NHS unless an individual application is made to the Cancer Drug Fund. The fund will give approval for first line treatment of advanced ovarian cancer based on the GOG 218 study that showed a progression free survival advantage of 14 months compared to 10 months with bevacizumab given during chemotherapy then as a single agent to 1 year. No overall survival advantage was found. The fund will also approve its use in the first line treatment of recurrent or metastatic cervical cancer, based on the GOG 240 study that showed a significantly improved overall survival of 17 vs 13.3 months when bevacizumab was given with platinum based chemotherapy. The side effects of bevacizumab include GI perforation (0.9%), haemorrhage (24%), severe hypertension (18%), nephrotic syndrome (7%), infusion reactions (3%), fistula (2%), thromboembolic events (2.6%) and non-healing wounds. Therefore it requires judicious use in women with potential serosal involvement of the bowel, and must not be used within 4 weeks of planned surgical treatment.
Targeted therapy Targeted drugs are a newer form of systemic treatment and are increasingly used for treatment of malignancy. These act on specific molecular targets involved in the growth or spread of cancer cells. As these targets are not found in high concentrations in normal cells the side effects are potentially fewer when compared to chemotherapy. When newer cancer drugs are licensed they first need to be approved by the relevant independent organisations before the NHS can routinely prescribe them. In England this is the National Institute for Health and Care Excellence (NICE). Arrangements are different in Wales and Northern Ireland but they often follow NICE guidance. Scotland has its own arrangements and uses the Scottish Medicines Consortium. Some drugs are not recommended by NICE, either because they have not yet been assessed,
Poly ADP ribose polymerase (PARP) Inhibitors: patients with BRCA 1 or 2 mutations have cancers with increased reliance on PARP (a cellular protein) to repair DNA. When a cell fails to repair the damaged DNA it dies. These patients show high response rates to PARP inhibitors such as olaparib or rucaparib. The SOLO1 phase III clinical trial investigated the effects of maintenance olaparib in patients with advanced ovarian cancer carrying the BRCA mutation. This trial showed that following first line platinum based treatment, addition of the oral PARP inhibitor olaparib for 2 years significantly improved 3 year disease free progression from 27% on placebo to 60%. Olaparib given in this context is now available in the UK via the cancer drug fund. The phase II clinical trial Study 191 evaluated the use of olaparib in patients with platinum-sensitive recurrent ovarian
Table 1
WHO Performance Status 1 Able to carry out all activity without restriction 2 Restricted strenuous activity but ambulatory and able to carry out light work 3 Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours 4 Symptomatic and in a chair or bed for more than 50% of the day but not bedridden 5 Completely disabled. Unable to carry out any self care. Totally confined to bed or chair Box 2
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sensitising the tumour cells to the effects of radiation and increasing tumour cell death rates.
cancer. This study showed that olaparib extended progression free survival from 4.3 to 11.2 months when compared with surveillance alone in BRCA mutated patients. Smaller benefits were seen in the BRCA wild type (non-mutated) patients. In the UK, NICE has approved olaparib in BRCA mutated patients with platinum sensitive disease after chemotherapy in a maintenance role in keeping with its license. Niraparib is another PARP inhibitor that is available for platinum sensitive recurrent ovarian high grade serous carcinoma after second line or later treatment in patients who have a partial or complete response to platinum based chemotherapy provided they have not had a PARP inhibitor before. It is available for both BRCA mutated and wild type patients, based on the NOVA study which showed an increased progression free survival in both groups, although the responses were more significant in the BRCA mutated group. PARP inhibitor side effects are usually mild to moderate and include fatigue (63%), nausea (77%), diarrhoea (34%), and anaemia (39%).
The planning process Prior to starting radiotherapy, most patients have a planning CT scan which is used to aid in the planning of their individualised treatments. The clinical oncologist or radiotherapy planner will evaluate the CT images alongside any diagnostic imaging, clinical pictures, and endoscopy reports, and then combine all the information to define the target area. The first step in planning is to define or delineate any visible tumour seen on imaging, and this is termed gross tumour volume (GTV). PET-CT and MRI scans can be fused with the planning CT scan to help define these target volumes. Next an additional margin is usually added around the gross visible tumour to account for microscopic spread and also expanded to include other areas at risk of disease. It is vital to be aware of the likely biological behaviour of the tumour and typical patterns of nodal spread, so that all ‘at risk’ areas may be included if needed. This volume is the clinical target volume (CTV), and it is possible to treat different CTV volumes with different doses, dependent upon their risk. A further margin is then added to give the final volume for planning and this is called the planning target volume (PTV). This margin accounts for daily changes in patient positioning during a typical course of treatment, and factors in alterations in the bladder and bowel filling for example, which can lead to variations in the position of pelvic organs each day (Figure 2). Within the pelvis, there are a number of organs which can be adversely affected by radiation and cause both acute (during treatment) and late toxicities (months or years later). These are termed organs at risk (OARs) and include the bladder, bowel, vagina and femoral heads. The radiation dose to these sensitive structures is minimised if possible, to reduce potential side effects, but it is likely that these structures will inevitably receive some radiation exposure. There is a risk of causing significant long-term side effects to the bladder and bowel in up to 15e20% of patients receiving a curative radiation dose for cervical cancers, but the risk of this side effect has to be weighed up against the risk and consequences of uncontrolled disease or recurrence. Long term late effects may also include stenosis of the vagina, bone pain, haematuria, early menopause/infertility and rectal bleeding.
Endocrine Therapy: endocrine or hormonal therapy aims to reduce the influence of oestrogen on cancer cell growth. Treatment is usually administered as oral tablets every day. They are usually a well-tolerated group of drugs, without the significant toxicities often associated with chemotherapy treatment. Tamoxifen is a selective oestrogen receptor modulator that competitively inhibits oestrogen binding to the oestrogen receptor. It has mixed antagonist and agonist activity depending on the target tissue. Letrozole is a non-steroidal aromatase inhibitor that blocks conversion of androgens into oestrogens in peripheral tissues. Megesterol acetate and medroxyprogesterone acetate are synthetic progestins. Their anti-cancer action is not completely understood. Possibilities include an effect at the pituitary level, reducing gonadotrophin production and therefore oestrogen production, and also local tissue effects at the oestrogen/progesterone receptors. For women with asymptomatic relapsed epithelial ovarian cancer, endocrine therapy may provide therapeutic benefit. Studies have shown that Letrozole has response rates of 9%, with stable disease in 42%. Tamoxifen has response rates of 10% with stable disease in 32% of patients. In women with relapsed endometrial cancer megestrol acetate, medroxyprogesterone acetate and tamoxifen have demonstrated activity in studies with reported response rates of up to 15e30%, predominantly in lower grade tumours.
Radiotherapy delivery Many centres in the UK deliver radiotherapy treatments via a plan made up of 3 or 4 treatment beams, delivered in an anteroposterior (AP) and right and left lateral beam arrangement. This leads to the highest dose being achieved in the middle of the patient in the region of a central tumour, but also can result in significant doses being deposited outside of the tumour, in the surrounding normal tissues such as the skin or bowel. The development of intensity-modulated radiotherapy (IMRT) has helped improve the coverage of deep-seated tumours in the pelvis by improving the dose-homogeneity and reducing high or low dose areas and allowing sharper dose-gradients to form at the tumour or target volume edges. This reduces the unwanted doses to the normal tissues outside of the target, and reduces the normal tissue toxicity effects. IMRT achieves this by increasing
Radiotherapy Radiotherapy utilises high energy x-rays which are generated by machines called linear accelerators (LINACs). Each treatment is known as a fraction. Fractions are usually delivered daily for five days (Monday to Friday) repeatedly over a course of a few weeks. This is typically 5 weeks for patients with gynaecological cancers receiving radical or adjuvant treatment. Sometimes chemotherapy is given concurrently with the radiotherapy (known as chemo-radiation), with the purpose of
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Repair - The above principle is known as repair. Fractionating the radiotherapy treatment allows time for sub-lethal damage to normal tissue cells to be repaired. Tumour cells are often unable to recover due to defects in their repair pathways. Re-oxygenation - Hypoxic cells are more resistant to the indirect effect of radiation, and this is the rationale for blood transfusions to maintain haemoglobin levels and therefore improve oxygen levels within the tumour. Redistribution e This refers to the effect that a fractionated radiation schedule has upon the timing of the tumour cell cycle, with multiple fractions more likely to catch the cells in a more sensitive part of the cycle. Figure 2 Radiotherapy planning CT scan showing volumes defined during planning process e GTV, CTV and final target volume e PTV.
Repopulation - Tumour cells can start to re-grow rapidly after around 4 weeks and therefore increasing the length between treatments may compound this effect and paradoxically increase tumour growth. Understanding repopulation underpins the need to complete a course of radiotherapy on time, with no delays, and the importance of not stopping treatment or missing fractions. Most radiotherapy fractions are delivered within 10e15 min but some of the newer techniques can take a little longer, for example if image-guidance is used (IGRT). This involves pretreatment imaging to ensure that the area being treated matches what was originally intended on the planning scan. These techniques may involve the matching of bony anatomy between the two scans and small moves can be made to the position of the patient to correct for any discrepancy prior to daily treatment. Patients receiving radical radiotherapy for cervical cancer may have variations in the amount of faeces and air present in the rectum each day, and bladder capacity often reduces during 5 weeks of treatment due to the effects of radiotherapy. This can affect the position of the cervix or target volume and potentially lead to a geographical miss unless not corrected for. This is where the role of image-guided radiotherapy can be vital in ensuring a radical dose is actually delivered to the tumour itself, and is increasingly important where higher ‘boost’ doses are delivered.
the number of radiation beams used to treat the tumour, sometimes using multiple mini beam-lets to enable this. One drawback to this modern technique is that a greater volume of normal tissue may be exposed to a lower dose than before, termed the low -dose bath effect, and this may contribute to a higher risk of second cancers in later life. This is a real issue for young patients receiving radical radiation courses, and second malignancies within a previous radiation field can be difficult to treat. Figure 3 shows an example of the dose distribution seen in a patient treated with IMRT. Mechanism of action of radiotherapy Radiotherapy aims to cause irreversible damage to the cell DNA by breaking the strands of the DNA helix which cannot be repaired, and therefore triggering the cell to apoptose when it attempts to replicate during mitosis. Double stranded DNA helix breaks are more likely to result in cell death than single strand breaks, because a remaining single DNA strand can act as a template for replication if it remains intact. There are five radio-biological principles known as the five R’s that account for how we deliver radiotherapy in practice, and how radiation influences tumour cells. The five Rs include e repair, re-oxygenation, re-distribution, radiosensitivity and re-population.
Brachytherapy The process of brachytherapy involves placing an internal applicator within a body cavity to enable a radioactive source to travel through it to the area requiring treatment. This could be the cervix itself or the vaginal vault if a hysterectomy has taken place. In endometrial cancer, brachytherapy to the vaginal vault is sometimes offered post-operatively to reduce the risk of local recurrence at this site. This practice is based on the PORTEC-2 trial showing a reduction in local recurrence and is typically offered to intermediate-risk endometrial cancers. No improvement in overall survival has been shown. Higher risk patients may be offered pelvic radiation to reduce pelvic recurrence risk. Current UK management of gynaecological cancers Ovarian, Tubal and Primary Peritoneal Tumours: early ovarian or tubal cancer (stage I and II) accounts for about 20% of all cases. Upfront surgery is the main treatment. Adjuvant
Figure 3 Intensity modulated radiotherapy of post-operative cervical cancer patient with nodal involvement. Note the colourwash dose distribution (red ¼ hottest, blue ¼ coolest dose) and coverage of the PTV45 e target volume, and relative sparing of the femoral heads.
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treatment with chemotherapy is delivered to high risk patients such as those with stage IC or II disease of any grade, clear cell or high grade tumours at any stage. The evidence for adjuvant treatment comes from meta-analyses including the Cochrane Review published in 2009, which showed a survival advantage for those with high risk features, or residual disease after surgery. The standard treatment is 6 cycles of carboplatin chemotherapy either as a single agent or in combination with paclitaxel. There is a lack of robust data on the best regimen and the current NICE guidance recommends single agent carboplatin. Advanced Ovarian Cancer (stage III and IV) is treated with primary surgery if the disease can be optimally de-bulked at that time (often stage IIIa and b), followed by adjuvant carboplatin and paclitaxel chemotherapy. If it is considered that optimal surgery is not achievable or appropriate in the upfront setting (often in extensive stage IIIc or IV disease) then neo-adjuvant carboplatin and paclitaxel is given for 3 cycles followed by interval cytoreductive surgery, and then a further 3 cycles of carboplatin and paclitaxel. Bevacizumab may be considered in addition, which would then continue as a maintenance treatment to complete 1 year. The PARP inhibitor olaparib has recently been approved for use as first-line maintenance treatment for women platinumsensitive disease who have the BRCA mutation, following their first course of chemotherapy. This has been shown to delay the onset of relapse and even has the potential to cure the disease. Unfortunately the majority of late stage ovarian cancer patients experience recurrence. There is a role for surgery in a minority of highly selected patients. However the management of relapse in most cases tends to be chemotherapy-based with the aim of treatment being disease and symptom control. If the patient has platinum-sensitive relapse (more than 6 months since previous platinum based treatment) then a combination of carboplatin with liposomal doxorubicin or gemcitabine can be used. If platinum-resistant (less than 6 months since the last platinum treatment) then liposomal doxorubicin or weekly paclitaxel are frequent choices of agent. Treatment is then delivered in an intermittent basis for as long as possible at times when the disease is rapidly progressing on CT or causing symptoms, aiming to preserve quality of life in addition to extending life. Hormonal treatments can also be used in this setting. PARP inhibitors can also be used for selected women who have platinum-sensitive disease following two courses of chemotherapy, irrespective of BRCA status. At present in the UK the 5-year survival for ovarian cancer overall is 46%.
surgery can be considered depending upon the tumour characteristics together with age or patient wishes, when a radical trachelectomy can be considered. Adjuvant chemo-radiotherapy is recommended for high risk patients with risk factors for recurrence. These include positive resection margin, unexpected lymph node involvement or parametrial invasion. There is a survival benefit with the addition of adjuvant chemo-radiation in this population. For those with intermediate risk factors such as tumour >4 cm, close vaginal margins, deep stromal invasion or the presence of lymphovascular space invasion (LVSI), (chemo-) radiation may also be considered to reduce the risk of pelvic recurrence. For the more advanced stage tumours >IB2, or in the presence of lymph node involvement then the standard of care is primary chemo-radiation. This can achieve high rates of local control even with stage IVA disease. In the UK, a typical treatment regime would be to deliver external beam radiotherapy (EBRT) at a dose of 45 Gy in 25 fractions across 5 weeks. The target volume would include the cervix, parametria, uterus and the pelvic nodes (and possibly PA nodes) at risk. IMRT techniques are increasingly used to deliver treatment, aiming to minimising radiation dose to the organs at risk, and in particular the bladder and bowel. Weekly cisplatin chemotherapy is given simultaneously as an intravenous infusion during the 5 week treatment regime, and is usually well tolerated although it does increase the risk of nausea and vomiting. The dose of radiation required to adequately treat cervical cancer is greater than that which can be delivered safely using external beam techniques alone, due to the radiation-sensitivity of the other pelvic structures. Patients on a radical treatment pathway therefore go on to receive brachytherapy immediately after their initial external beam treatment. This enables a tumoricidal dose to be achieved at the tumour/cervix, and it can be delivered with an acceptable level of normal tissue damage. Brachytherapy involves placement of applicators directly into the cervix/uterus to enable a radioactive source to be positioned within the applications, and therefore deliver a high radiation dose to the target. This can be carried out in a number of ways, and in our centre involves an inpatient admission with 3 or 4 fractions delivered over a number of days. The radiation delivery planning process involves a team of specialist physicists, radiographers and clinical oncologists and can be complex and often requires both MRI and CT imaging. Palliative courses of radiotherapy to control local disease, usually without chemotherapy, can be offered to patients who have metastatic disease, or who are not fit enough for radical treatment. Controlling pelvic disease with radiotherapy even in metastatic disease may still be recommended, as poorly controlled pelvic disease can be unpleasant and difficult to manage. For metastatic cervix cancer, palliative chemotherapy may also be considered. Platinum based combination chemotherapy is recommended. The addition of bevacizumab adds a small survival benefit.
Cervical tumours: planning treatment for cervical cancer requires accurate clinical staging of cervical tumours, and examination under anaesthesia (EUA) often forms part of the clinical staging, except in the earliest stages with small tumour. Early stage tumours beyond stage 1A1 and up to stage 1B1 (confined to the cervix and <4 cm) which are node negative, can be managed surgically and the standard operation would be a radical hysterectomy with or without bilateral salpingooophorectomy. Ovarian metastases are rare and the ovaries are usually conserved in younger patients. Pelvic lymphadenectomy is carried out to aid surgical staging and guide the need for postoperative adjuvant treatment. In selected cases fertility sparing
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Endometrial cancer The mainstay of endometrial cancer treatment remains surgery and usually involves a hysterectomy and bilateral salpingooophrectomy with or without regional lymph node staging.
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not possible. The radiotherapy dose would need to be at least 60 e65Gy, and if fit enough, chemotherapy with cisplatin would be given concurrently. The traditional approach would be to offer 45Gy to the pelvis over 5 weeks followed by a boost to the residual gross tumour. IMRT may be an alternative approach if available, and may allow delivery of a higher simultaneous boost dose to the primary tumour during delivery of pelvic radiotherapy.
Omental biopsy and biopsies of any suspicious pelvic or intraabdominal lesions may be appropriate in selected cases to aid in surgical staging. Patients with advanced disease may sometimes be offered cytoreductive surgery, even though surgery is unlikely to be curative (stages III-IVA), as there may be a survival benefit and palliation in those with minimal gross residual disease. In the presence of extra-pelvic metastatic disease, treatment is palliative and surgery may or may not be required depending upon the individual symptoms. In these circumstances chemotherapy may be appropriate for palliation only. Those with early stage disease (IA) without significant risk factors do not require adjuvant treatment, but those with intermediate or high risk factors should be considered for adjuvant radiotherapy and/or chemotherapy. Those with an intermediate risk of recurrence may benefit from adjuvant brachytherapy to the vaginal vault. This reduces local recurrence only at the vault and has no impact upon survival. Those with greater risk factors such as higher stages and or grade of tumour, and presence of LVSI may benefit from adjuvant pelvic radiotherapy to reduce the risk of a pelvic recurrence. Pelvic radiotherapy has not been shown to improve overall survival but comes with greater toxicity compared with brachytherapy alone. Adjuvant chemotherapy with carboplatin and paclitaxel in combination is frequently given prior to pelvic radiotherapy in those deemed to be at high risk of recurrence. The PORTEC 3 study showed that overall those that had chemotherapy in addition to radiotherapy had an improved 5 year overall survial of 5%. The greatest benefits were seen in those with stage 3 disease or serous histology. The same platinum doublet may be offered in metastatic disease to help palliate symptoms and typically 6 cycles may be delivered. For those with more indolent disease, lower grade tumours and those expressing oestrogen receptors (ER) or progesterone receptor (PR) positivity, hormonal therapy such as Megace may induce a response. A small percentage of patients may have a prolonged remission period. The Mirena IUS is sometimes used alone in patients with early stage, low grade disease who are unfit for treatment, or who still require fertility.
Vaginal tumours Vaginal tumours are rare. EUA is vital for planning purposes. Tumours within proximal (upper) two thirds of the vagina are usually treated in a similar manner as cervical tumours, often with radical chemo-radiation. Those in the distal third of the vagina are usually managed like vulval cancers. A FURTHER READING Tewari KS, Sill MW, Long 3rd HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014; 370: 734. NICE Clinical Guideline CG122: ovarian cancer: recognition and initial management, April 2011. Published. Reducing uncertainties about the effects of chemo radiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev, 2010 Jan 20; https://doi.org/10.1002/ 14651858.CD008285. CD008285. Tanner EJ, Leitao Jr MM, Garg K, et al. The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma. Gynecol Oncol 2011 Dec; 123: 548e52. Epub 2011 Sep. 25.
Practice Points C
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Vulval tumours Vulval cancers are typically squamous cell carcinomas, and if caught early are best managed surgically. The operation entails a radical local excision or radical modified vulvectomy and the assessment of lymph node (LN) involvement is important prognostically. Those with stage IB disease or above and no palpable nodes require LN assessment either with sentinel node biopsy or node dissection. Positive margins should be re-excised where possible although radiotherapy can be an alternative to reduce risk of recurrence and should also be considered in cases with close margins, big tumours >4 cm and those with node positive disease. Primary chemo-radiation can be an option in patients unfit for surgery or in locally advanced disease where clear margins are
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Carboplatin in combination with paclitaxel is the most commonly used regimen in gynaecological malignancy. Candidates for chemotherapy should be of WHO performance status 0e2, with adequate renal, hepatic and haematological function. Treatment delivered to individuals outside these specifications can lead to increased morbidity or mortality. The developments of targeted agents are changing practice in the management of gynaecological tumours and have lower rates of toxicity compared to chemotherapy. Dose dense and intraperitoneal chemotherapy are not standard first line treatment options in the UK at present. Pelvic radiotherapy following a hysterectomy for endometrial cancer reduces the risk of local recurrence but does not impact on overall survival The standard radical treatment of cervical tumours greater than stage IB2, or with lymph node involvement is 5 weeks of radiotherapy with weekly cisplatin followed by brachytherapy to boost the tumour dose which may require an inpatient stay.
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