concentration and may be of particular value in preventing
complications following treatment of leukaemias or bulky
All cytotoxic drugs except vincristine sulfate p. 929 and
bleomycin p. 919 cause bone-marrow suppression. This
commonly occurs 7 to 10 days after administration, but is
delayed for certain drugs, such as carmustine p. 893,
lomustine p. 897, and melphalan p. 897. Peripheral blood
counts must be checked before each treatment, and doses
should be reduced or therapy delayed if bone-marrow has
Cytotoxic drugs may be contra-indicated in patients with
acute infection; any infection should be treated before, or
when starting, cytotoxic drugs.
Fever in a neutropenic patient (neutrophil count less than
/litre) requires immediate broad-spectrum
antibacterial therapy. Appropriate bacteriological
investigations should be conducted as soon as possible.
Patients taking cytotoxic drugs who have signs or symptoms
of infection should be advised to seek prompt medical
attention. All patients should initially be investigated and
treated under the supervision of the appropriate oncology or
In selected patients, the duration and the severity of
neutropenia can be reduced by the use of recombinant
human granulocyte-colony stimulating factors.
Symptomatic anaemia is usually treated with red blood cell
transfusions. For guidance on the use of erythropoietins in
patients with cancer, see MHRA/CHM advice and NICE
Reversible hair loss is a common complication, although it
varies in degree between drugs and individual patients. No
pharmacological methods of preventing this are available.
Venous thromboembolism can be a complication of cancer
itself, but chemotherapy increases the risk.
Cytotoxic drugs: effect on pregnancy and
Most cytotoxic drugs are teratogenic and should not be
administered during pregnancy, especially during the first
trimester. Considerable caution is necessary if a pregnant
woman presents with cancer requiring chemotherapy, and
specialist advice should always be sought.
Exclude pregnancy before treatment with cytotoxic drugs.
Contraceptive advice should be given before cytotoxic
therapy begins- women of childbearing age should use
effective contraception during and after treatment.
Regimens that do not contain an alkylating drug or
procarbazine may have less effect on fertility, but those with
an alkylating drug or procarbazine carry the risk of causing
permanent male sterility (there is no effect on potency).
Pretreatment counselling and consideration of sperm
storage may be appropriate. Women are less severely
affected, though the span of reproductive life may be
shortened by the onset of a premature menopause. No
increase in fetal abnormalities or abortion rate has been
recorded in patients who remain fertile after cytotoxic
Cytotoxic drugs: nausea and vomiting
Nausea and vomiting cause considerable distress to many
patients who receive chemotherapy and to a lesser extent
abdominal radiotherapy, and may lead to refusal of further
treatment; prophylaxis of nausea and vomiting is therefore
extremely important. Symptoms may be acute (occurring
within 24 hours of treatment), delayed (first occurring more
than 24 hours after treatment), or anticipatory (occurring
prior to subsequent doses). Delayed and anticipatory
symptoms are more difficult to control than acute symptoms
and require different management.
Patients vary in their susceptibility to drug-induced
nausea and vomiting; those affected more often include
women, patients under 50 years of age, anxious patients, and
those who experience motion sickness. Susceptibility also
increases with repeated exposure to the cytotoxic drug.
Drugs may be divided according to their emetogenic
potential and some examples are given below, but the
symptoms vary according to the dose, to other drugs
administered and to the individual’s susceptibility to
Mildly emetogenic treatment—fluorouracil, etoposide
p. 923, methotrexate p. 913 (less than 100 mg/m2
in children), the vinca alkaloids, and abdominal
Moderately emetogenic treatment—the taxanes, doxorubicin
hydrochloride p. 901, intermediate and low doses of
cyclophosphamide p. 894, mitoxantrone p. 903, and high
doses of methotrexate (0.1– 1.2 g/m2
Highly emetogenic treatment— cisplatin p. 921, dacarbazine
p. 895, and high doses of cyclophosphamide.
For patients at low risk of emesis, pretreatment with
dexamethasone p. 675 or lorazepam p. 339 may be used.
For patients at high risk of emesis, a 5HT3-receptor
antagonist, usually given by mouth in combination with
dexamethasone and the neurokinin receptor antagonist
aprepitant p. 433 is effective.
Prevention of delayed symptoms
For delayed symptoms associated with moderately
emetogenic chemotherapy, a combination of
dexamethasone and 5HT3-receptor antagonist is effective;
for highly emetogenic chemotherapy, a combination of
dexamethasone and aprepitant is effective. Rolapitant p. 434
and metoclopramide hydrochloride p. 432 are also licensed
for delayed chemotherapy-induced nausea and vomiting.
Prevention of anticipatory symptoms
Good symptom control is the best way to prevent
anticipatory symptoms. Lorazepam can be helpful for its
amnesic, sedative, and anxiolytic effects.
Treatment of cytotoxic-induced side-effects
Anthracycline-induced cardiotoxicity
Local guidelines for the management of extravasation
should be followed or specialist advice sought.
See further information on the prevention and
management of extravasation injury.
Chemotherapy-induced mucositis and myelosuppression
Folinic acid p. 941 (given as calcium folinate) is used to
counteract the folate-antagonist action of methotrexate
p. 913 and thus speed recovery from methotrexate-induced
mucositis or myelosuppression (‘folinic acid rescue’).
Folinic acid is also used in the management of
methotrexate overdose, together with other measures to
maintain fluid and electrolyte balance, and to manage
Folinic acid does not counteract the antibacterial activity
of folate antagonists such as trimethoprim p. 574.
When folinic acid and fluorouracil p. 910 are used together
in metastatic colorectal cancer the response-rate improves
compared to that with fluorouracil alone.
The calcium salt of levofolinic acid p. 942, a single isomer
of folinic acid, is also used for rescue therapy following
methotrexate administration, for cases of methotrexate
overdose, and for use with fluorouracil for colorectal cancer.
890 Cytotoxic responsive malignancy BNF 78
Immune system and malignant disease
The dose of calcium levofolinate is generally half that of
The disodium salts of folinic acid and levofolinic acid are
also used for rescue therapy following methotrexate therapy,
and for use with fluorouracil for colorectal cancer.
Haemorrhagic cystitis is a common manifestation of
urothelial toxicity which occurs with the oxazaphosphorines,
cyclophosphamide p. 894 and ifosfamide p. 896; it is caused
by the metabolite acrolein. Mesna p. 940 reacts specifically
with this metabolite in the urinary tract, preventing toxicity.
Mesna is used routinely (preferably by mouth) in patients
receiving ifosfamide, and in patients receiving
cyclophosphamide by the intravenous route at a high dose
(e.g. more than 2 g) or in those who experienced urothelial
toxicity when given cyclophosphamide previously.
Anthracyclines and other cytotoxic antibiotics
Drugs in this group are widely used. Many cytotoxic
antibiotics act as radiomimetics and simultaneous use of
radiotherapy should be avoided because it may markedly
increased toxicity. Daunorubicin p. 900, doxorubicin
hydrochloride p. 901, epirubicin hydrochloride p. 902 and
idarubicin hydrochloride p. 903 are anthracycline antibiotics.
Mitoxantrone p. 903 is an anthracycline derivative.
Doxorubicin hydrochloride is available as both
conventional and liposomal formulations. The different
formulations vary in their licensed indications,
pharmacokinetics, dosage and administration, and are not
interchangeable. Conventional doxorubicin hydrochloride is
solid tumours including breast cancer.
Epirubicin hydrochloride is structurally related to
doxorubicin hydrochloride and can be used to treat breast
Idarubicin hydrochloride has general properties similar to
those of doxorubicin hydrochloride; it is mostly used in the
treatment of haematological malignancies.
Daunorubicin also has general properties similar to those
Mitoxantrone is structurally related to doxorubicin
Pixantrone p. 904 is licensed as monotherapy for the
as a fifth-line or greater chemotherapy in refractory patients
Bleomycin p. 919 is given intravenously or intramuscularly
to treat metastatic germ cell cancer and, in some regimens,
Dactinomycin is principally used to treat paediatric
cancers. Its side-effects are similar to those of doxorubicin,
except that cardiac toxicity is not a problem.
Mitomycin p. 919 can be given intravenously to treat
gastro-intestinal and breast cancers, and by bladder
instillation for superficial bladder tumours. It causes delayed
The vinca alkaloids, vinblastine sulfate p. 929, vincristine
sulfate p. 929, and vindesine sulfate p. 930, are used to treat
a variety of cancers including leukaemias, lymphomas, and
some solid tumours. Vinorelbine p. 931 is a semi-synthetic
vinca alkaloid. See also, role of vinorelbine in the treatment
Antimetabolites are incorporated into new nuclear material
or combine irreversibly with cellular enzymes, preventing
Extensive experience is available with these drugs, which are
among the most widely used in cancer chemotherapy. They
act by damaging DNA, thus interfering with cell replication.
Cyclophosphamide is used mainly in combination with
other agents for treating a wide range of malignancies,
including some leukaemias, lymphomas, and solid tumours.
It is given by mouth or intravenously; it is inactive until
Ifosfamide is related to cyclophosphamide and is given
Melphalan p. 897 is licensed for the treatment of multiple
myeloma, polycythaemia vera, childhood neuroblastoma,
advanced ovarian adenocarcinoma, and advanced breast
cancer. However, in practice, melphalan is rarely used for
ovarian adenocarcinoma; it is no longer used for advanced
breast cancer. Melphalan is also licensed for regional arterial
perfusion in localised malignant melanoma of the
extremities and localised soft-tissue sarcoma of the
Lomustine p. 897 is a lipid-soluble nitrosourea and the
drug is given at intervals of 4 to 6 weeks.
Carmustine p. 893 has similar activity to lomustine; it is
given to patients with multiple myeloma, non-Hodgkin’s
lymphomas, and brain tumours. Carmustine implants are
licensed for intralesional use in adults for the treatment of
recurrent glioblastoma multiforme as an adjunct to surgery.
Carmustine implants are also licensed for high-grade
malignant glioma as adjunctive treatment to surgery and
Estramustine phosphate p. 896 is a combination of an
oestrogen and chlormethine used predominantly in prostate
cancer. It is given by mouth and has both an antimitotic
effect and (by reducing testosterone concentration) a
Mitobronitol is occasionally used to treat chronic myeloid
leukaemia; it is available on a named-patient basis from
specialist importing companies.
ANTINEOPLASTIC DRUGS › ALKYLATING AGENTS
Bendamustine hydrochloride 05-Jun-2018
Treatment of chronic lymphocytic leukaemia | Treatment
of non-Hodgkin’s lymphoma | Treatment of multiple
▶ Adult: (consult local protocol)
MHRA/CHM ADVICE: BENDAMUSTINE (LEVACT ®): INCREASED
MORTALITY OBSERVED IN RECENT CLINICAL STUDIES IN OFFLABEL USE; MONITOR FOR OPPORTUNISTIC INFECTIONS,
HEPATITIS B REACTIVATION (JULY 2017)
Recent clinical trials have shown increased mortality
when bendamustine was used in combination
treatments outside its approved indications. In addition,
a recent European review of post-marketing data has
suggested that the risk of opportunistic infections for all
patients receiving bendamustine treatment may be
greater than previously recognised.
The MHRA recommends monitoring patients for
opportunistic infections as well as cardiac, neurological,
and respiratory adverse events; known carriers of
hepatitis B virus (HBV) should be monitored for signs
and symptoms of active HBV infection. Patients should
be advised to report promptly new signs of infection;
consider discontinuing bendamustine if there are signs
BNF 78 Cytotoxic responsive malignancy 891
Immune system and malignant disease
l CONTRA-INDICATIONS Jaundice . low leucocyte count. low
platelet count. major surgery less than 30 days before start
of treatment. severe bone marrow suppression
l CAUTIONS Cardiac disorders—monitor serum potassium
l INTERACTIONS → Appendix 1: alkylating agents
system disorder. paraesthesia . peripheral neuropathy . sepsis .taste altered
▶ Frequency not known Extravasation necrosis . hepatic
failure . necrosis .renal failure . severe cutaneous adverse
SIDE-EFFECTS, FURTHER INFORMATION Secondary
malignancy Use of bendamustine is associated with an
increased incidence of acute leukaemias.
Infections Serious and fatal infections are reported,
including opportunistic infections such as Pneumocystis
jirovecii pneumonia (PJP), varicella zoster virus (VZV) and
cytomegalovirus (CMV)—manufacturer advises
monitoring for respiratory signs and symptoms
throughout treatment; patients should be advised to
report new signs of infection, including fever or
respiratory symptoms, promptly. Reactivation of hepatitis
B is reported in patients who are chronic carriers of the
virus—manufacturer advises monitoring for signs and
symptoms of active hepatitis B during treatment and for
several months after stopping treatment.
l CONCEPTION AND CONTRACEPTION Effective
contraception is required during treatment in men or
women, and for 6 months after treatment in men. See also
Pregnancy and reproductive function in Cytotoxic drugs
l PREGNANCY Avoid (teratogenic and mutagenic in animal
studies). See also Pregnancy and reproductive function in
l BREAST FEEDING Discontinue breast-feeding.
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment—no information available.
Dose adjustments Manufacturer advises reduce dose by
l RENAL IMPAIRMENT No information available on use in
patients with creatinine clearance less than 10 mL/minute.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Bendamustine for the first-line treatment of chronic
lymphocytic leukaemia (February 2011) NICE TA216
stage B or C) in patients for whom fludarabine
combination chemotherapy is not appropriate.
www.nice.org.uk/guidance/TA216
▶ Obinutuzumab with bendamustine for treating follicular
lymphoma refractory to rituximab (August 2017) NICE TA472
Bendamustine in combination with obinutuzumab
followed by obinutuzumab maintenance, is recommended
for use within the Cancer Drugs Fund as an option for
treating adults with follicular lymphoma that did not
respond or progressed during or up to 6 months after
treatment with rituximab or a rituximab-containing
regimen, only if the conditions in the managed access
agreement for obinutuzumab are followed.
www.nice.org.uk/guidance/TA472
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (April 2011)
that bendamustine (Levact ®) is accepted for use within
NHS Scotland for first-line treatment of chronic
lymphocytic leukaemia (Binet stage B or C) in patients for
whom fludarabine combination chemotherapy is not
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
Powder for solution for infusion
▶ Bendamustine hydrochloride (Non-proprietary)
Bendamustine hydrochloride 25 mg Bendamustine 25mg powder
for concentrate for solution for infusion vials | 1 vial P £6.85–
£65.98 | 5 vial P £312.53–£347.26 (Hospital only) | 20 vial P £1,241.14 (Hospital only)
Bendamustine hydrochloride 100 mg Bendamustine 100mg
▶ Levact (Napp Pharmaceuticals Ltd)
Bendamustine hydrochloride 25 mg Levact 25mg powder for
concentrate for solution for infusion vials | 5 vial P £347.26
Bendamustine hydrochloride 100 mg Levact 100mg powder for
concentrate for solution for infusion vials | 5 vial P £1,379.04
Chronic myeloid leukaemia, induction of remission
▶ Adult: 60 micrograms/kg daily (max. per dose 4 mg);
Conditioning treatment before haematopoietic progenitor
▶ BY MOUTH, OR BY INTRAVENOUS INFUSION
▶ Adult: (consult local protocol)
Conditioning treatment before haematopoietic progenitor
cell transplantation in patients who are candidates for a
reduced-intensity conditioning (RIC) regimen
▶ Adult: (consult local protocol)
DOSES AT EXTREMES OF BODY-WEIGHT
▶ Dose may need to be calculated based on body surface
area or adjusted ideal body weight in obese patients—
RISKS OF INCORRECT DOSING OF ORAL ANTI-CANCER MEDICINES
l CAUTIONS Avoid in Acute porphyrias p. 1058 . high dose
(antiepileptic prophylaxis required). history of seizures
(antiepileptic prophylaxis required). ineffective once in
blast crisis phase . previous progenitor cell transplant
NTERACTIONS → Appendix 1: monoclonal antibodies
BNF 78 Antibody responsive malignancy 877
Immune system and malignant disease
▶ Uncommon Angioedema . cyanosis . infusion related
reaction . nasal dryness . onycholysis .respiratory disorders
▶ Rare or very rare Anaphylactic reaction . severe cutaneous
l CONCEPTION AND CONTRACEPTION Manufacturer advises
effective contraception during and for 6 months after
l PREGNANCY Avoid (toxicity in animal studies). See also
Pregnancy and reproductive function in Cytotoxic drugs
l BREAST FEEDING Manufacturer advises avoid
breastfeeding during and for 2 months after treatment.
l PRE-TREATMENT SCREENING Evidence of non-mutated
RAS status (at exons 2, 3 and 4 of KRAS and NRAS) is
required before panitumumab treatment is initiated, and
should be determined by an experienced laboratory using a
▶ Monitor for hypomagnesaemia.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Cetuximab, bevacizumab and panitumumab for the treatment
of metastatic colorectal cancer after first-line chemotherapy
Panitinumab monotherapy is not recommended for the
treatment of patients with metastatic colorectal cancer
that has progressed after first-line chemotherapy.
www.nice.org.uk/guidance/TA242
▶ Cetuximab and panitumumab for previously untreated
metastatic colorectal cancer (updated September 2017)
Panitumumab is recommended, within its marketing
authorisation, as an option for previously untreated RAS
wild-type metastatic colorectal cancer in adults in
. 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX), or
. 5-fluorouracil, folinic acid and irinotecan (FOLFIRI).
This advice is contingent upon the manufacturer providing
panitumumab with the discount agreed in the patient
www.nice.org.uk/guidance/TA439
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
ELECTROLYTES: May contain Sodium
Panitumumab 20 mg per 1 ml Vectibix 400mg/20ml concentrate for
solution for infusion vials | 1 vial P £1,517.16 (Hospital only)
Vectibix 100mg/5ml concentrate for solution for infusion vials | 1 vial P £379.29 (Hospital only)
l DRUG ACTION Pembrolizumab is a monoclonal antibody,
which binds to the programmed death-1 (PD-1) receptor,
thereby potentiating an immune response to tumour cells.
Melanoma (specialist use only)| Non-small cell lung cancer
(specialist use only)| Urothelial carcinoma (specialist
use only)| Classical Hodgkin lymphoma (specialist use
only)| Head and neck squamous cell carcinoma
▶ Adult: 200 mg every 3 weeks, for dose adjustments due
to side-effects or infusion-related reactions—consult
MHRA/CHM ADVICE: PEMBROLIZUMAB (KEYTRUDA ®): REPORTS
OF ORGAN TRANSPLANT REJECTION (JULY 2017)
A European review of worldwide data concluded that
pembrolizumab may increase the risk of rejection in
organ transplant recipients. The MHRA recommends
considering the benefit of treatment with
pembrolizumab versus the risk of possible organ
transplant rejection for each patient.
l CAUTIONS Patients may need pretreatment to minimise
the development of adverse reactions (consult product
l INTERACTIONS → Appendix 1: monoclonal antibodies
(SCARs). skin reactions .taste altered . vomiting
▶ Uncommon Adrenal insufficiency . alopecia . decreased
▶ Rare or very rare Erythema nodosum . haemolytic anaemia . myasthenic syndrome . sarcoidosis
▶ Frequency not known Solid organ transplant rejection
SIDE-EFFECTS, FURTHER INFORMATION Immune-related
reactions Most immune-related adverse reactions are
reversible and managed by temporarily stopping treatment
and administration of a corticosteroid—consult product
literature for further information.
Infusion-related reactions Manufacturer advises to
permanently discontinue treatment in patients with severe
l CONCEPTION AND CONTRACEPTION Manufacturer
recommends effective contraception during treatment and
for at least 4 months after treatment in women of
l PREGNANCY Manufacturer advises avoid unless potential
benefit outweighs risk—no information available
l BREAST FEEDING Manufacturer advises avoid—no
l MONITORING REQUIREMENTS Manufacturer advises
monitor for signs and symptoms of infusion- and immunerelated reactions.
878 Antibody responsive malignancy BNF 78
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