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REVIEW

Principles of chemotherapy
and radiotherapy

for hysterectomy. 5-year survival figures for this group of patients, as reported from Manchester, were 72%. Radiotherapy
may be offered on a selective basis to patients after hysterectomy
for endometrial cancer. The PORTEC-2 and the MRC ASTEC trial
show no survival advantage for routine external beam radiotherapy for patients with low or intermediate risk stage IB
tumour. There is some evidence of survival advantage for patients with G3 stage Ib and stage II tumour for post-operative
radiotherapy.
Where cure is impossible, radiotherapy can be a very useful
treatment for palliation. Pain from bony metastasis can be eased
in 80% and abolished in 50% of patients receiving a single X-ray
treatment, and vaginal bleeding from advanced pelvic malignancy can also be controlled with palliative radiotherapy.

Tessa A Greenhalgh
R Paul Symonds

Abstract
The management of most malignancies is multidisciplinary with chemotherapy and radiotherapy widely employed. The reasons tumours are
destroyed and normal tissues recover after radiotherapy are complex
and thought to be due to differences in intrinsic radiosensitivity and ability to repair and repopulate. Linear accelerators, which produce skinsparing photons (high energy X-rays), are used to treat deep-seated tumours. Brachytherapy (short distance treatment) with implanted or internal radiation sources can also be used.
Chemotherapy consists of drugs of different classes and modes of action, which may be used in combination to prevent drug resistance. Cytotoxic agents affect normal and malignant cells leading to a variety of sideeffects. Chemotherapy can be given with radiotherapy to enhance the
therapeutic effect. With advances in the understanding of the molecular
biology of cancer, targeted therapies are now being used in clinical practice. Chemotherapy can be used with curative or palliative intent.

Keywords

cancer;

cervix;

chemotherapy;

endometrium;

The biological basis of radiotherapy treatment


The reasons why tumours are destroyed and normal tissues
recover following radiotherapy are complex and poorly understood. Radiation kills cells by the production of secondary
charged particles and free radicals, which interact with the
nucleic acids. Cellular lethality seems to be related to the number
of double-stranded DNA breaks produced in the nucleus. The
sensitivity of tissues to radiotherapy seems to depend on their
ability to repair radiation damage, repopulate and reoxygenate.
The capacity to repair double and single strand DNA breaks
varies between normal tissue and different tumours. The ability
to repopulate is important, as cells can rapidly divide to replace
cells killed by radiation. Normal tissues such as the buccal mucosa and bone marrow have a considerable number of cells in the
G0 resting phase of the cell cycle; these can be rapidly stimulated
to divide and replace dead cells. Unfortunately, welldifferentiated and moderately well-differentiated squamous carcinomas of the head and neck region have a marked ability to
repopulate and this may account for radiation failure in the
treatment of some of these tumours. As tumours grow, new
blood vessels develop to feed the neoplasm. By and large, the
new blood vessels are primitive in nature and the blood supply is
inadequate to supply the growing tumour. Necrotic areas
develop within such tumours which contain hypoxic cells and
are a source of radioresistance. However, during a course of
radiotherapy cells that were hypoxic may reoxygenate and
become more radiosensitive.

ovary;

radiotherapy

Radiotherapy
Radiotherapy is the art of using ionizing radiation to destroy
malignant tumours whilst minimizing damage to normal tissues.
It can be highly effective. Retrospective studies have shown cure
rates of 80e85% following radiotherapy treatment of stage Ib
carcinoma of the cervix. A large randomized controlled trial
carried out in north Italy showed identical survival figures for
patients with operable cervical cancer (stage Ib-IIa) treated either
by Wertheims hysterectomy or radical radiotherapy. Interestingly, the serious complication rate was higher in patients treated
by surgery or surgery plus radiotherapy rather than radiotherapy
alone.
Up to 1999 radical radiotherapy alone was the treatment of
choice for stages 2b-4a carcinoma of the cervix. More recently
studies have shown that radiotherapy given concurrently with
platinum based chemotherapy can increase disease-free survival
and overall survival in these patients and this has been adopted
as the standard treatment in patients suitable for concurrent
therapy. Radiotherapy is also used as an alternative to surgery in
patients with early endometrial carcinoma who are unsuitable

Radiation dosage
The interaction of radiation with tissues is measured as the
absorbed dose, which is the quantity of energy absorbed per unit
mass. In the SI system of units this is measured as joules per
kilogram. One joule/kg is 1 Gray (Gy). 1 Gy is equal to 100 rad
(the previous unit for radiation dose).
The limitation on radiation dose, when given in an attempt to
cure a tumour, is the risk of normal tissue damage. This damage
is seen initially as acute radiation effects in rapidly proliferating
cells such a skin epithelium, mucosal lining of the upper digestive tract, or the surface lining of the small bowel. This may
manifest itself as moist desquamation of the skin, mucositis inside the mouth or diarrhoea caused by damage to jejunal crypt
cells. This damage normally heals. The greater concern is the risk
of late damage to normal tissue. This appears 9 months to 5 years
after treatment due to effects on slowly proliferating tissue,

Tessa A Greenhalgh MBChB MRCP(UK) FRCR is a Clinical Oncology Specialty


Trainee at Leicester Royal Infirmary, Leicester, UK. Conflicts of interest:
none declared.
R Paul Symonds MD FRCP FRCR is Professor of Clinical Oncology at the
University of Leicester, Leicester, UK. Conflicts of interest: none
declared.

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particularly vascular endothelium. This is expressed as progressive fibrosis and arteritis leading to necrosis, fistulae or stricture.
The serious complication rate for patients treated for carcinoma
of the cervix by radical radiotherapy is about 5%. Newer developments in radiotherapy like intensity modulated radiotherapy (IMRT) should be able minimize these side effects.

significant difference between LDR and HDR in terms of overall


survival and toxicity except for slight increase in small bowel
toxicity with HDR.
Current developments in radiotherapy
The vast improvement in diagnostic imaging has been
immensely helpful in radiation treatment planning. With the use
of reconstructed matched computed tomograms and magnetic
resonance images the accuracy of treatment planning can be
improved and this reduces the possibility of a geographical
miss. Moreover, the dose distribution to the target volume can
be shaped to conform tightly to the shape of the tumour,
reducing the volume of normal tissue irradiated by up to 50%.
The risk of late damage (side effects developing months or years
following radiotherapy treatment) can therefore be reduced and
the dose given to the tumour can be increased with a greater
probability of tumour control. This conformal radiotherapy is
possible due to the introduction of the multi-leaf collimator. This
is an apparatus in the head of the linear accelerator made up of
pairs of tungsten bars (5e10 mm width). These can move
independently to shape the treatment beam to irregular contours.
Conformal radiotherapy is now the standard treatment for many
solid cancers. Prospective dose escalation studies in prostate
cancer showed that higher doses could be given using this
technique with better tumour outcomes and no increase in late
toxicity. Early dose escalation trials are underway in cervical
cancer using intensity modulated radiotherapy (IMRT).

The therapeutic ratio


The therapeutic ratio has been defined as the relationship between the desired and unwanted effects of therapy. One method
to reduce the risk of normal tissue injury and increase the therapeutic ratio is to fractionate treatment. The total dose of radiation to be delivered is divided into 20e30 separate treatments
and given daily over 4e6 weeks. An alternative approach is to
administer continuous radiation directly into or adjacent to the
tumour. Such treatments are referred to as brachytherapy (short
distance treatment).
Radiotherapy machines
Modern radiotherapy departments use linear accelerators, which
are used to produce X-rays of energies of 6e20 million electron volts
(MeV). Such X-rays have major clinical advantages over low energy
X-rays generated by older kilovoltage machines. Mega-voltage Xrays are relatively skin-sparing. It is fairly easy to treat deep-seated
tumours with a homogeneous radiation beam and the radiation dose
to bone no higher than surrounding tissues. Older kilovoltage
apparatus generates X-rays of 100,000e300,000 electron volts
(KeV). These machines produce X-rays only 2e3 times more energetic than those used to take diagnostic radiographs. The maximum
energy of the kilovoltage X-rays is deposited on the skin surface, this
meant their usefulness is limited in treating deeper tumours. At
present these machines are used for low dose palliative treatments
or for the treatment of skin/superficial tumours.

IMRT
IMRT is a more advanced form of conformal radiotherapy.
Currently many centres in the UK are not using this routinely in
the treatment of gynaecological malignancies but it is increasingly a subject of interest and research. The main interest is in
improving radiation treatment for cervical carcinoma by
reducing bowel and urinary toxicity whilst looking at the possibility of increasing dose to the primary and areas at risk. There
are studies which looked at IMRT boost as an alternative to
brachytherapy but because of the increase in the size of treatment volume, brachytherapy still remains the method of choice.
From the technical point of view, IMRT takes more time and
needs specialist physics staff to plan the treatment. It involves
careful delineation of areas at risk by the clinician and very
precise radiotherapy beam arrangements. It can be quite time
consuming especially with regards to radiotherapy quality
assurance. Hopefully with increasing experience these drawbacks will be minimized.

Brachytherapy
Brachytherapy involves implantation or insertion of radioactive
seeds or sources directly into or adjacent to the tumour (or
tumour bed). It allows a high radiation dose to the tumour with
low doses to surrounding tissue to reduce toxicity. It is an
essential part of the radiation therapy for carcinoma of the cervix
and may also be used in the treatment of endometrial carcinoma.
The patient has hollow tubes placed into the uterus (usually
under general anaesthetic) or vagina. The current practice is to
use an afterloading device which is able to move the radioactive
sources remotely from a machine into the intra-uterine or vaginal
applicators and back out again at a prescribed time to deliver the
appropriate radiation dose. The patient is kept in isolation during
the treatment but the sources can be moved back into the machines at the touch of a button in the case of emergency. Newer
trial evidence (PORTEC-2) suggests that brachytherapy offers
comparative reduction in local recurrence in intermediate risk
endometrial cancer with better quality of life, shorter duration of
treatment and reduced toxicity especially with relation to
gastrointestinal side effects from external beam radiotherapy.
In the UK the practice has been low to medium dose rate
brachytherapy using radioactive Caesium with treatment times of
18e36 hours. However increasingly centres are switching to high
dose rate brachytherapy (HDR) using Iridium sources with
treatment given over minutes. A meta-analysis has suggested no

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IGRT
Image guided radiotherapy (IGRT) is now being introduced,
using 3D imaging to plan treatment which allows greater accuracy and the potential for dose escalation whilst reducing dose to
vulnerable organs such as bladder and bowel. Organ motion in
the pelvis, particularly of the uterus can vary as much as 4 cm.
Daily CT imaging, usually using the radiotherapy machine, can
correct discrepancies when treating with external beam radiotherapy. Image guided brachytherapy requires imaging of patients with CT or MRI once the applicators are in situ.
Calculations are then made to optimize dose by varying the position and dwell time of the radioactive seeds. It is suggested that

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REVIEW

this will have a beneficial effect on local control and toxicity and
is being increasingly used in the UK.

preferred to cisplatin due to equivalent efficacy and better


toxicity profile. Scheduling of paclitaxel dosing was assessed in
ovarian, fallopian tube and primary peritoneal cancers. Weekly
paclitaxel plus carboplatin 3 weekly led to statistically improved
overall survival compared to conventional 3 weekly paclitaxel/
carboplatin. Intraperitoneal (IP) therapy leads to higher drug
concentrations in the abdominal cavity compared to systemic
administration. GOG 172 trial suggested a significant survival
benefit for IP compared to IV chemotherapy in cytoreduced
ovarian cancer. Unfortunately the increased toxicity seen with IP
and weekly paclitaxel schedules currently limits their use.
The relapse free interval after platinum therapy is predictive
of further benefit of platinum chemotherapy. An interval of more
than 6 months signifies a chance of further response, often using
a platinum doublet. If platinum-resistant then paclitaxel, pegylated liposomal doxorubicin (PLD) or topotecan (a topoisomerase inhibitor) are options.

Chemotherapy
Introduction
Whilst surgery and radiotherapy are essentially local treatments
directed at the primary tumour, chemotherapy is a systemic treatment for metastases (See Table 1). Where chemotherapy is used in
the curative setting, it is essential to maintain dose and schedule as
dose delays or reductions can compromise long-term outcome. In
the palliative setting to ensure quality of life dose modifications may
be required. Cytotoxic chemotherapy aims to kill tumour cells whilst
relatively sparing normal cells. The sensitivity of tumours varies by
histology and class of drugs with high cure rates in tumours highly
sensitive to the drugs administered.
Clinical use of chemotherapy
The most common use of chemotherapy is in the treatment of
disseminated disease and in gynaecological cancers is in inoperable or metastatic ovarian tumours. Here response rates for
chemo-naive patients can be 60e70% for platinum based
chemotherapy agents and palliates symptoms such as bowel
obstruction and ascites.

Cervical cancer: indications for chemotherapy include concurrent


chemoradiation for locally advanced disease based on five randomized trials showing up to 50% decrease in the risk of death
compared to radiotherapy alone. A UK national audit of patients
with cervical cancer treated with either chemoradiation or radiotherapy alone showed that the addition of cisplatin substantially
improves prognosis. Of current interest is the use of neoadjuvant
chemotherapy to make the cancer resectable. In a Cochrane metaanalysis overall and progression free survival were improved with
neoadjuvant chemotherapy in both early and locally advanced
disease albeit based on a small number of trials. Whether this
approach is equivalent to chemoradiotherapy is being addressed in
two Phase III trials (EORTC 55994 and NCT00193739). The current
UK trial for patients with locally advanced cervical cancer (Interlace)
involves treatment with either weekly cisplatin and radiation alone
or induction chemotherapy (carboplatin/paclitaxel) followed by
standard chemoradiation.

Ovarian cancers: two large randomized studies (ICON 1 and


ACTION) compared adjuvant chemotherapy (platinum based)
with no immediate chemotherapy in early stage epithelial
ovarian cancer. In both trials, recurrence-free survival was
significantly better with chemotherapy. A combined analysis
showed a significantly better 5-year overall survival (82% versus
74%) making adjuvant chemotherapy standard after optimal
resection (except low risk disease). Primary surgical cytoreduction followed by chemotherapy is the preferred management
for stage III/IV ovarian cancer. However, inoperable patients
may receive chemotherapy followed by interval debulking if
there is a good response to treatment. Neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy (EORTC 55971,
CHORUS trials). Platinum/paclitaxel is currently the chemotherapy of choice (GOG 111 and OV-10 trials) with carboplatin

Endometrial cancer: chemotherapy is used in the adjuvant setting


for advanced disease or palliative setting, cisplatin/doxorubicin or
carboplatin/paclitaxel. Adjuvant therapy for early stage high-risk
cancer is controversial as adjuvant chemotherapy alone may not
provide sufficient locoregional control. Randomized trials have
addressed the combination of chemotherapy plus radiotherapy. A
Phase III study (NSGO-EC-9501/EORTC 55991) included patients
with surgical stage I, II, IIIA (positive peritoneal fluid cytology only),
or IIIC (positive pelvic lymph nodes only) and high risk for micrometastatic disease. Patients were randomized to pelvic radiotherapy
(brachytherapy) or to chemotherapy before or after radiotherapy.
A significant 38% reduction in progression with combined therapy
was seen, but only a trend towards better overall survival. Pooled
analysis including data from this trial confirmed these results
whereas a separate Finnish study found no benefit. The role of
combined treatment may be indicated by the PORTEC-3 study
which recently closed to recruitment. This randomized patients with
intermediate risk disease to concurrent chemoradiotherapy plus
adjuvant chemotherapy versus radiotherapy alone.

Indications for chemotherapy


Curative
intent

Palliative
intent

Radical

Treating chemosensitive tumours


e.g. advanced testicular, lymphoma
Neoadjuvant Prior to definitive treatment (surgery,
radiotherapy)
e.g. reducing sarcoma size to allow limbsparing surgery
Adjuvant
Following definitive treatment
e.g. treating micrometastatic disease in
Dukes C colorectal cancer
Concurrent With radiotherapy as a sensitizing agent
to improve therapeutic effects
e.g. cervical carcinoma
Palliative
Symptom control

Assessment of response to chemotherapy


Tumour shrinkage (objective response) and disease progression
are useful endpoints in clinical trials. Response Evaluation

Table 1

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type. Response rates of 20% or more are usually considered


clinically useful and sometimes randomized between a new and
standard treatment or placebo.
Phase III trials tend to be large randomized studies where the
new drug may be used alone or in combination and usually
compared against standard therapy. These trials may also be
used to assess different doses or ways of giving a standard
treatment. Phase III trials usually involve many patients (thousands). Success rates between the different study arms may be
small so many patients are needed to show a difference.
To overcome possible intrinsic or acquired resistance, drugs are
usually given in combinations (up to four). Basic principles of
combination therapy include single agent activity against the
tumour and non-overlapping mechanisms of action. Multiple drug
regimes reduce the risk of resistant clones of cells emerging. In
addition drugs should have non-overlapping toxicity and be
administered in the most intensive way possible with the shortest
interval between treatments to allow recovery of normal tissues.
Chemotherapy is usually administered in 3-weekly cycles although
optimum administration may require shorter intervals. Methotrexate may be given every 3 days in the treatment of choriocarcinoma and cisplatin is given weekly when combined with
radiotherapy in the radical treatment of cervical cancer. Topotecan
is much better tolerated when given weekly instead of 3 weekly.

Criteria in Solid Tumours (RECIST) defines response, stable


disease and progression during treatment. A complete response
is the disappearance of all measurable or evaluable disease,
signs, symptoms and biochemical changes related to the tumour
maintained for at least 4 weeks. A partial response is a reduction
of at least 30% of the sum of the longest diameters of all target
lesions compared with pre-treatment measurements, and for the
response to be maintained for at least 4 weeks. Typical response
rates for effective chemotherapy regimens (e.g. carboplatin/
paclitaxel for ovarian cancers) are 60e70%.
The smallest detectable tumour measuring 1 cubic centimetre
contains about 100,000,000 (109) cancer cells. Not all of these
cells are viable and it is the clonogenic cell component that must
be sterilized. However, a 99.9999% cell kill is only a cellular
reduction of five logarithms. If there were initially 1011 cells, 106
cells will remain. A million cancer cells may be clinically undetectable but in time this tumour will re-grow. In some cases,
however, all of the clonogenic cells are sterilized resulting in a
clinical cure.
Selection of patients for chemotherapy
Selecting patients takes into consideration performance status,
comorbidities, patients wishes and risk/benefit ratio balancing
the aim of treatment versus acute/long term side effects. Patients
vary in their life priorities with some patients accepting a treatment with significant morbidity for a small chance of cure. For
others this would be unacceptable.
Some general principles are useful. Age is a useful guide with
physiological age more important than chronological. Patients in
their 80s with ovarian cancer can tolerate carboplatin chemotherapy. Performance status (see Table 2) is one of the most
important predictors of outcome from chemotherapy. Higher
response rates are seen in ambulant compared to bed-bound patients and chemotherapy is generally not indicated if performance
status >2. An exception is a gynaecological malignancy presenting
as sub-acute intestinal obstruction where chemotherapy may
relieve the obstruction. In addition a third of patients have a sustained response. Usually chemotherapy is not as effective for bowel
obstruction if the patient is not chemo-naive. The response to previous chemotherapy and duration of remission is useful in assessing
whether there is likely to be a response to second line therapy. After
completion of platinum chemotherapy, the chance of a response is
around 20% and 60% if relapse is within 6 and after 12 months
respectively. Patients with ovarian cancer who progress on platinum based chemotherapy have a very poor prognosis.

Chemotherapy and the cell cycle


The rate of tumour growth reflects the proportion of actively
dividing cells, length of the cell cycle, and rate of cell loss. Variations
in these factors are responsible for the variable rates of growth
observed among tumours of different histologies, as well as among
metastatic and primary tumours of the same histology. Tumours
generally exhibit a sigmoid shaped growth curve in which tumour
doubling times vary with tumour size. Growth rate is usually most
rapid at small volumes and slows as the tumour becomes larger due
to cell loss and lack of blood and oxygen supply.
Tumour cells do not divide faster than their normal tissue
equivalents, however, there are usually more cells dividing in a
tumour than within normal tissues. The growth fraction exceptionally can approach 100% in rapidly growing tumours (Burkitts lymphoma). By contrast, in slow growing tumours (some
breast and colon cancers), growth fraction is <20%. Actively
proliferating cells are most vulnerable to chemotherapy.
The cycle is divided into four main phases (see Table 3). The
G0 phase is important. Such cells are not undergoing cell division
and may eventually suffer programmed cell death (apoptosis).
However, following treatment with chemotherapy or radiotherapy some G0 cells may be recruited back into cycle.
The mode of action of chemotherapeutics can be divided into cell
cycle specific and non specific. For specific drugs the lethal effects
vary between different phases of the cell cycle (Figure 1), being most
effective in tumours with a high mitotic rate. They produce the
greatest cell kill if given in prolonged exposure (e.g. antimetabolites
and the S phase). Other examples include etoposide, vinca alkaloids
and taxanes (G2/M phase). In contrast, non-specific drugs are lethal
throughout the cell cycle and cell kill is linked to total dose rather
than prolonged administration. The distinction between specific
and non-specific drugs is over simplified as the non-specific drugs
cisplatin, carboplatin and alkylating agents are particularly active in
G2 and at the G1/S boundary.

Selection of chemotherapeutic drugs


The time for a new drug to come into common use is generally
long. Initially new drugs are tested in a variety of tumour types in
Phase I trials (w30 patients). Patients are recruited in cohorts,
the first given a dose where no toxicity is expected and then the
dose is increased until the maximally tolerated dose is reached.
Patients typically have advanced cancers and have already
received all standard treatments. Although these trials concentrate on toxicity and optimal dose, occasionally responses are
noted and this gives indications for Phase II trials.
Relatively small numbers of patients (up to 100) are recruited
in Phase II studies. Their aim is to assess if a treatment has potential benefit and usually concentrate on a particular tumour

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enzyme dihydrofolate reductase, leads to inhibition of DNA and


RNA synthesis. Toxicity can be inhibited by the timely administration of folinic acid. Methotrexate has a limited role in treatment of gynaecological cancers. Other agents include 5-FU,
where cytotoxicity is also through inhibition of the enzyme
thymidylate synthetase. Capecitabine, an oral prodrug of 5-FU
requires metabolism to the active form and in combination
with epirubicin and cisplatin (ECX) has activity in relapsed
ovarian cancer. Gemcitabine, an analogue of deoxycytidine is a
prodrug requiring phosphorylation to its active form and has
activity in platinum and taxane-resistant ovarian cancer.

Performance status
0

Fully active, able to carry our all activities


without restriction
Restricted in physically strenuous activity but
ambulatory and able to carry out work of a
light or sedentary nature
Ambulatory and capable of all self-care but
unable to carry out any work activities; up and
about more than 50% of waking hours
Capable of only limited self-care; confined to
bed or chair 50% or more of waking hours
Completely disabled; cannot carry out any
self-care; totally confined to bed or chair

3
4

Antitumour antibiotics: the most important members of this


drug class are the anthracyclines (doxorubicin and epirubicin).
They inhibit DNA synthesis through a complex series of actions.
They are used in the treatment of breast cancer and uterine
sarcomas. Pegylated liposomal doxorubicin (PLD) is a formulation that captures the active drug in liposomes producing a slow
release preparation with increased activity. This changes the side
effect profile, with doxorubicin causing myelosuppression and
hair loss and PLD causing a hand and foot syndrome.
Bleomycin can produce strand breaks in both the DNA of the
nucleus and mitochondria and is most commonly used in the
treatment of germ cell tumours and malignant pleural infusions.
Vinca alkaloids (vincristine and vinblastine) are extracted from
the periwinkle and act against the mitotic spindle to treat a wide
variety of malignancies. Etoposide, clinically the most important
podophyllotoxin has activity against germ cell tumours, some
sarcomas and ovarian tumours.

Table 2

Therapeutic agents used in the treatment of gynaecological


cancer
Alkylating agents: DNA replication is inhibited by this group of
drugs by the drug forming covalent bonds with DNA bases. Some
are bifunctional and react with two strands of DNA to produce a
cross linkage. The role of alkylating agents in the treatment of
gynaecological cancer has diminished. There are a number of
alkylating agents available with varying toxicity. Chlorambucil is
the least toxic and can be given by mouth. This drug still has a
limited role in the treatment of frail patients with ovarian cancer.
Cyclophosphamide and ifosfamide have activity against ovarian
cancer and squamous carcinomas of cervix and vulva. Both produce
an acrolein metabolite, which can cause haemorrhagic cystitis.

Taxanes: the taxane group is extracted from the yew tree.


Paclitaxel is isolated from bark of the Western Yew tree and
docetaxel from the needles of the European Yew tree. Both act
against micro-tubules to induce a sustained block in mitosis and
have equal activity in the treatment of ovarian cancer, with
different toxicities. Taxanes are used with gemcitabine in
relapsed uterine leiomyosarcoma. Both taxanes can lead to immediate allergic reactions and even anaphylaxis. High doses of
steroids are given for 24 hours before chemotherapy to prevent
these reactions.

Platinum compounds: cisplatin and carboplatin are highly


effective in the treatment of gynaecological cancers. Platinum
compounds are cycle non-specific and form DNA cross-links by
an action similar to the bifunctional alkylating agents. The DNA
lesions produced are frequent and difficult to repair. In comparison with cisplatin, carboplatin has a lower incidence of side
effects (nausea, vomiting, hearing loss, peripheral neuropathy
and renal toxicity) but causes more myelosuppression. Both
agents are renally excreted and neither cause hair loss. Cisplatin
is the most active agent in the treatment of cervical cancer in
conjunction with radiotherapy. Carboplatin is useful in the
treatment of ovarian cancer and tolerated by the elderly.

Chemotherapy toxicity
The pattern of toxicity varies between different chemotherapy
drugs and even between members of the same drug class.

Antimetabolites: antimetabolites work by inhibiting essential


biosynthetic processes or by being incorporated into RNA or
DNA. Methotrexate is an antifolate which, by blocking the

Bone marrow suppression: many agents affect the rapidly


dividing cells in the bone marrow leading to temporary bone
marrow suppression. Lowest white cell and platelet counts (nadir
values) are usually seen 10 days after treatment with alkylating
agents or anthracyclines. Interestingly, the addition of paclitaxel
to carboplatin reduces the degree of thrombocytopenia. The
nadir count after carboplatin is usually 15e18 days after treatment. Cisplatin is considerably less myelosuppressive than carboplatin but long term use can lead to anaemia. The vinca
alkaloids and bleomycin are particularly non-myelosuppressive.
Granulocyte colony stimulating factors can reduce the duration
of neutropenia and incidence of febrile neutropenia and are
indicated if risk of febrile neutropenia is 20% or greater when
dose maintenance important.

Cell cycle
G1

Gap 1

S
G2
M
G0

Synthesis
Gap 2
Mitosis
Resting phase

Metabolic changes in preparation for cell


division
DNA synthesis
Preparation for mitosis
Nuclear division followed by cellular division
Non-dividing cells

Table 3

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Antitumour antibiotics
(Doxorubicin)
Antimetabolites
(Methotrexate)
S
(2-6h)

Vinca
alkaloids
(Vinorelbine)

G2
(2-32h)

M
(0.5-2h)

Alkylating agents
(Ifosfamide)

Mitotic
inhibitors

Taxoids
(Paclitaxel)

G1
(2-+h)

G0

Figure 1 Chemotherapy activity and the cell cycle.

Nausea and vomiting: 5HT3 antagonists granisetron or ondansetron in combination with corticosteroids have markedly
reduced the frequency of nausea and vomiting associated with
chemotherapy. Carboplatin chemotherapy for ovarian cancer
tends not to cause emesis. Cisplatin, doxorubicin and ifosfamide
are amongst the most emetogenic drugs although usually prevented. Recently neurokinin-1 antagonists have been introduced
(aprepitant).

can cause a cardiomyopathy leading to conduction problems in


the heart and congestive cardiac failure, usually seen when the
cumulative dose approaches 450e550 mg/m2. The doxorubicin analogue, epirubicin is less cardio-toxic. Patients with
pre-existing cardiac disease are at increased risk. Cardiotoxicity is a concern as these drugs are used in the curative
setting such as the treatment of breast cancer. These patients
may also receive trastuzumab, another agent with risk of
cardio-toxicity.

Alopecia: temporary hair loss is thought to occur due to direct


toxic insult on rapidly dividing hair follicle cells. Incidence with
cyclophosphamide, doxorubicin, etoposide and taxanes is high
compared to carboplatin/cisplatin. Risk can be reduced by scalp
cooling although only effective in drugs with a relatively short
half-life (doxorubicin) as it is difficult to tolerate the cooling
device for more than 1 hour.

Neurotoxicity: chemotherapy induced peripheral neuropathy is


associated with symmetrical progressive onset of sensory
symptoms in a glove and stocking distribution: paresthesia, hyperesthesia, hypoesthesia, dysesthesia, usually appearing in the
toes/feet before involvement in fingers/hands. Loss of tendon
reflexes, sensory deficit and dysfunction signal greater damage.
The underlying mechanism is unclear and seen following
vincristine, paclitaxel and occasionally cisplatin. Docetaxel is
significantly less neurotoxic than paclitaxel although tends to be
more myelosuppressive. Ifosfamide can cause an encephalopathy leading to confusion or even a coma but this is usually
reversible.

Renal toxicity: the kidneys are the major excretory organs for
many drugs. Both methotrexate and cisplatin can cause severe
damage to the renal tubules. Renal toxicity occurs in a third of
patients after cisplatin administration but is largely preventable
by adequate pre and post chemotherapy hydration with saline.
Hypomagnesaemia can occur with cisplatin, usually recovering
within a month of stopping treatment. Carboplatin normally does
not affect the kidneys.

Late effects on the ovaries: many alkylating agents appear to


produce permanent gonadal failure in women. Procarbazine is
the agent most likely to cause ovarian failure. 5-FU, methotrexate, doxorubicin and cisplatin doses less than 450 mg/m2 are
not associated with permanent ovarian failure.

Cardio-toxicity: the myocardium has limited regenerative


capability and is therefore susceptible to damage. Doxorubicin

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264

2014 Elsevier Ltd. All rights reserved.

REVIEW

Current developments in systemic therapy


Biological/targeted therapy: recent major advances have been
seen with targeted therapies. Targets include growth factor receptors, signalling molecules, cell cycle proteins, modulators of
apoptosis and angiogenesis generally specific to cancer cells.
Their advantage is better tolerability compared to chemotherapy
drugs although some patients can develop severe toxicity. One is
of the best known is Trastuzumab (Herceptin), which targets the
HER-2 receptor expressed in around 20% of breast cancer cells,
significantly improving progression free survival (PFS) and
overall survival.
Targeted therapies are now in routine use in the treatment of
ovarian cancer. Bevacizumab is a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) and
prevents binding to its receptor. Randomized control trials have
demonstrated a benefit in PFS in combination with platinum
doublet in chemo-naive patients (GOG218, ICON7) and
platinum-sensitive recurrent disease (OCEANS). The addition of
maintenance bevacizumab following combination therapy appears to be an important contributor to the 4 months improvement in median PFS when compared with chemotherapy alone.
The toxicity of biological agents differs from that of chemotherapy. For bevacizumab, these include hypertension, thrombotic events, proteinuria, bleeding, altered wound healing and
gastrointestinal perforation. This should be taken into account if
surgery if being planned. More recent evidence in a Phase III trial
(GOG240) has suggested an overall survival benefit and
improved response rate with adding bevacizumab to chemotherapy for recurrent and metastatic cervical cancer. Toxicity
was increased, in particular bleeding, thromboembolism and GI
fistula.
Other anti-VEGF agents under investigation include cediranib
which has demonstrated an overall survival benefit in relapsed
platinum sensitive ovarian cancer (ICON 6). The CIRCCa trial is
looking at cediranib in combination with chemotherapy for
metastatic/relapsed cervical cancer and results are awaited. PolyADP ribose polymerase (PARP) inhibitors (e.g. olaparib) exploit
synthetic lethality by targeting specific DNA repair pathways.
Phase II trials showed activity in hereditary ovarian cancer
(BRCA1/2 mutations). As many epithelial ovarian cancers are
defective in their ability to repair DNA damage ongoing trials are
investigating their role in high-grade serous epithelial cancers
and platinum-resistant disease.

FURTHER READING
1 Hogberg T. Adjuvant chemotherapy in endometrial carcinoma: overview
of randomised trials. Clin Oncol (R Coll Radiol) 2008 Aug; 20: 463e9.
2 Kong A, Powell M, Blake P. The role of postoperative radiotherapy in
carcinoma of the endometrium. Clin Oncol (R Coll Radiol) 2008 Aug;
20: 457e62.
3 DSouza DP, Rumble RB, Fyles A, Yaremko B, Warde P. Intensitymodulated radiotherapy in the treatment of gynaecological cancers.
Clin Oncol (R Coll Radiol) 2012 Sept; 24: 499e507.
4 Sadozye AH, Reed NA. A review of recent developments in imageguided radiation therapy in cervix cancer. Curr Oncol Rep 2012 Dec;
14: 519e26.
5 Tierney JF, Vale C, Symonds P. Concomitant and neoadjuvant chemotherapy for cervical cancer. Clin Oncol (R Coll Radiol) 2008 Aug; 20:
401e16.
6 Vale CL, Tierney JF, Davidson SE, Drinkwater KJ, Symonds P. Substantial
improvement in UK cervical cancer survival with chemoradiotherapy:
results of a royal college of radiologists audit. Clin Oncol 2010 Sept;
22: 590e601.
7 Suh DH, Kim JW, Kim K, Kim HJ, Lee KH. Major clinical research advances in gynecologic cancer in 2012. J Gynecol Oncol 2013 Jan; 24: 66
e82.

Practice points
C

Ongoing trials
The INTERLACE trial is a Phase III multicentre trial of weekly
induction chemotherapy using paclitaxel and carboplatin, followed by standard chemoradiation vs. standard chemoradiation
alone in patients with locally advanced cervical cancer. ICON8 is
another Phase III trial currently recruiting patients with FIGO
stage Ic-IV ovarian cancer. Initial randomization is to immediate
or delayed primary surgery. Patients are then randomized to six
cycles of 3-weekly carboplatin and paclitaxel (standard), 3weekly carboplatin with weekly paclitaxel or both agents given
weekly. Those in the delayed surgery group have their operation
after three cycles of chemotherapy then complete the final three
cycles.
A

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265

Radiotherapy is as effective as radical hysterectomy in the treatment of stage 1b cervical cancer.


Concurrent chemotherapy and radiotherapy is the treatment of
choice for stages 2b-4a carcinoma of cervix and the chemotherapy
schedule is weekly cisplatin. Intra-uterine and intra-vaginal
brachytherapy are an essential part of any radiotherapy regimen
used to treat cervical cancer.
Patients suffering from carcinoma of endometrium who are
medically unfit for hysterectomy can be treated successfully by
radiotherapy. Pelvic recurrences following hysterectomy for carcinoma of endometrium can be reduced by post-operative
radiotherapy.
Treatment of endometrial cancer is changing; post-operative
chemotherapy in high-grade endometrial cancers significantly
improves progression free survival and overall survival. In intermediate grade endometrial cancers, post-operative brachytherapy
seems to give same benefit but better quality of life compared to
external beam radiotherapy.
Pain from bone metastasis can be reduced or eliminated in 80%
of patients by a single X-ray treatment.
Except for the treatment of choriocarcinoma, where cure rates are
very high, the main role of chemotherapy in gynaecological cancer
is palliation.
Stage 3 is the most common stage at diagnosis of ovarian carcinoma and the 5-year survival is only 20e30%, however, median
survival is now 3 years. The response rate to carboplatin or carboplatin and paclitaxel is 60e70%.
Recent research has shown that 5-year survival for stage 1
ovarian cancer patients can be increased by 10% by the addition
of chemotherapy following surgery.
Bevacizumab improves progression free survival in advanced
ovarian cancer when combined with chemotherapy.

2014 Elsevier Ltd. All rights reserved.