Cancer chemotherapy

Chemotherapy (cancer chemotherapy) is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen.

Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles; this results in the most common side effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).

Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy and is technically not chemotherapy.


From the very beginning of its evolution, cancer can present remote metastases. It is therefore resistant to local treatment (such as surgery or radiotherapy). Medical treatment of cancer, particularly anti-cancer chemotherapy, is prescribed in order to impede such evolution.

We now know a great deal about the action of chemotherapy and the rules for prescribing it, but in many circumstances, experimental questions remain for which precise data collection is needed in order to optimise its use.

Molecular biology discoveries made in the 1970’s following President Nixon’s Cancer Plan are now producing (30 years later!) new therapeutic avenues without a cytotoxic effect on the cells. Rather than destroying cancerous cells, they endeavour to slow down their metastatic evolution or the development of remote metastases, thus reducing their death potential.

General principles

Main chemotherapy drugs  :

                Anti-metabolite 

               Alkylating agents

                                               Modifying agents of the tertiary structure of DNA
                                               
                                             Diverse Agents acting on DNA

                                             Mitotic spindle poisons

Taxanes

Chemotherapy Indications

Curative Intent
Adjuvant and neo-adjuvant Intent
Palliative Intent
Experimental chemotherapy

Principles for poly-chemotherapy

Chemotherapy Toxicity

Acute non specific toxicity
Chronic specific toxicity

Practical aspects of chemotherapy

The chemotherapy protocol
Chemotherapy Prescription
Chemotherapy Administration

Chemotherapy resistance

Although I have tried to regularly update this teaching website, it is quite possible that new medications or new indications are not yet described. On the other hand, the exchange of personal points of view has always been one of the bases of this course. I would therefore be very grateful for any kind comments in order to improve this work.

This is also, and first and foremost, a French website and slight differences may exist among the various English speaking countries in terms of indication, dosage and brand names of chemotherapy products.

Conclusions:

Anticancer chemotherapy should be integrated into a multidisciplinary approach and cannot be considered following the conclusion of one isolated (however excellent he/she may be) physician!
Being often under experimentation, it is at best conducted within research or evaluation networks.

In spite of remarkable progress and the incredible hopes (and fears) of patients, chemotherapy remains, for many major cancers (like lung, head and neck, colon, ovary or kidney) a therapy offering modest results. The medical oncologist should therefore remain modest in his (her) approach.

Chemotherapy requires quite a range of aptitudes, and therefore a motivated and attentive medical team, with trained nursing staff, meticulous pharmacists, and experienced assistants.

Psychological aspects of patient care should also be taken into account throughout treatment: the frontier between curative and palliative treatment is often blurred.

General principles of chemotherapy (1)  :


An explanation of a few general principles allows improved understanding of anticancer chemotherapy:

• In a tumour, only the cells which have the capacity to indefinitely reproduce themselves (stem cells) are dangerous. These are the cells that we intend to kill. The other cells, those which multiply themselves but cannot reproduce more than a few generations and those which are very well differentiated and cannot divide, will eventually die naturally without chemotherapy.

Theoretical composition of a tumour: from the top: stem cells which renew themselves indefinitely, then multiplying cells, then differentiating cells which result in cell death.

• We do not possess genuinely specific drugs for cancer cells: each drug that we use is more or less toxic for normal cells.
  
• Most of the drugs (at least in classical chemotherapy) will kill the cancer cells when they are dividing by altering the delicate mechanisms of cell division. Slowly developing tumours are therefore less concerned. Conversely, highly proliferating healthy tissue (like blood cell lineages, mucosa cells, skin) are particularly concerned and should regenerate in order to maintain the patient alive. All our drugs have a more or less marked haematological toxicity and most often other form(s) of chronic toxicity.

		In relation to the cell proliferation capacity, the number of dead cells (on the vertical axis) is more important for proliferating tumours (in red). However most drugs only act during a period of the cell cycle. Thus, a cell cycle dependant antimitotic drug will produce a plateau after the initial decrease in the number of the cells. (on the vertical axis: number of cells, on the horizontal axis: time after chemotherapy treatment).

General principles of chemotherapy (3):

The importance of cellular irrigation

If the cancer cells are poorly irrigated, they become quiescent (this is observed in the centre of the tumour). They also will receive less anticancer drugs and will be less sensitive to them.

This is one of the reasons why an initial surgical procedure to reduce the tumour volume is so important (as in ovarian carcinoma).

On the other hand, radiotherapy strongly modifies the vascularisation of and around the tumour. If relapse occurs inside the irradiated volume, the relapsing tumour is generally chemoresistant, due to deficient vascularisation (and perhaps also because of similar cross-resistance mechanisms between chemotherapy and radiotherapy).

Access to tumour cells is of utmost importance in order to eradicate them via chemotherapy.

A blood-brain barrier has been described which often renders cerebral tumours and metastases very resistant to chemotherapy due to the absence of penetration of the drug inside the tumour. Most anticancer drugs are large and very complex molecules with low solubility. Only small liposoluble molecules can cross this blood-brain barrier (however they may be difficult to transport by plasma).

There are breakages in this blood-brain barrier inside the tumour, however generally speaking, brain tumours are poorly irrigated, with central necrosis, and are therefore not penetrated by anticancer drugs brought by the blood stream.



Diagram representation of the blood-brain barrier. The endothelial cells of the capillaries (CE) are joined together by tight junctions (TJ) which can only be crossed by small molecules coming from the vascular lumen. The astrocyte feet are also joined by Gap junctions (GJ) which can be only crossed by lipophilic molecules towards the extracellular space where a neuron has been drawn.

Conversely, the use of intraperitoneal chemotherapy should allow an increased concentration of the drug close to the peritoneal metastases among ovarian or digestive tumours. However, this contact chemotherapy cannot penetrate a depth of more than a few millimetres, thus limiting the procedure.

Main drugs: antimetabolites (1) :


They inhibit the synthesis of nucleic acids, the first necessary step for any cell multiplication. These drugs can be divided into two sub-classes:

• inhibitors of necessary enzymes, of which methotrexate is the prototype,
• lure drugs

A third class of drugs can also be considered, represented solely by L-Asparaginase which depletes circulating L-asparagine, thus depriving the cancer cells.

Antifolic drugs

Several antifolic drugs are now available, of which methotrexate is the prototype.

Methotrexate

It inhibits the folinic acid synthesis necessary for nucleic basis synthesis (uridine and thymidine), by combining with dihydrofolatereductase.

Diagram of the action of methotexate: as an inhibitor of dihydrofolatereductase, it prevents the activity of thymidilate synthetase necessary for the incorporation of nucleotide dTMP into DNA. The massive supply of folinic acid reverses its action and the combination enables more powerful chemotherapy.

Methotrexate can be used:

• either at standard doses, alone (30 to 50 mg/m²)

• or at very high dose, which can approach several grams, with the consecutive administration of its antidote, folinic acid.

This technique requires the use of repeated serum measurements of Methotrexate.
The activity of Methotrexate varies considerably depending on the dose (see page with detailed description of this product ).

Other antifolic drugs

An antifolic analogue of methotrexate now exists: raltitrexed, (Tomudex ™) the major indication of wich is the colon tumour.
Another drug whose indications are currently under exploration is pemetrexed (Alimta™) currently indicated in mesotheliomas..

Main drugs: antimetabolites (2) :

Lure drugs

These are fraudulent molecules, which, because of their chemical similarity to necessary intermediary metabolic components, are accepted as a substrate by cells and inhibit the biosynthesis of nucleic acids and proteins necessary for cell division.

Diagram of the action of antimetabolites which cannot be integrated in the DNA strand hence preventing cellular division.

We can distinguish

Antipyrimidic drugs.

These drugs resemble cytosine, thymine or uracile.

There are some standard examples:

• 5-Fluoro-Uracile
• Cytosine Arabinoside

And more recently synthesised products with different activities:

• Gemcitabine
• Capecitabine
• Tegafur-Uracile

Antipuric drugs

These drugs resemble guanine or adenine.

There are some standard examples:

• 6 Mercapto-Purine
• Thio-Guanine

And more recently synthesised molecules with different activities:

• Cladribine
• Fludarabine
• Pentostatine

5-FU has a more complex action mechanism than Methotrexate but also modifies the folate pathway (for this reason, it is often associated with folinic acid in FUFOL protocols for digestive tumours).

Diagram showing the action of 5-FU. It also inhibits thymidilate synthetase. The supply of folinic acid improves folate metabolism thus strengthening the action of 5-FU.

Most of these molecules will be subjected to the intracellular enzymatic transformations of normal nucleotides and in particular for cytosine arabinoside the formation of complex mono-, then bi-, then tri-phosphorylated. Conversely they may also be deaminated thus rendering them inactive. It is therefore necessary to maintain a high level of dosage in order to saturate cellular metabolisms.

Importance of phosphorylation and deamination metabolism in antimetabolite activity.

The deamination process is used by capecitabine to get 5-FU.

DNA structure modifying agents :

Normal DNA comprises not only its primary structure built of a succession of nucleic bases, and not only its secondary structure which is built of the loose crosslinks between its two strands, but also a tertiary structure involving a specific and mobile coiling, the configuration of which is necessary for transcription and replication.

Winding of double strand DNA around the nucleosome	DNA supercoiling and nucleosomes in a chromosome

Two kinds of interaction have been described at this level:

• activation and blocking of topoisomerase II, an enzyme which allows rapid DNA unwinding via specific cuts and restitution of the tertiary structure.
• intercalation of plane chemical products between DNA twists, thus rendering the DNA molecule stiff and incapable of transcription or replication

Moreover, other mechanisms may interfere with certain molecules (for instance production of free radicals by anthracyclins).

Anti-topo-isomerases I  :

Topoisomerases are the indispensable enzymes enabling DNA to loosen its incredible winding and coiling before transcription or replication can occur.

Two kinds of topo-isomerase can be distinguished:

• Type I topoisomerases which only concern one DNA strand allowing the passage of a strand through a dedicated 'hole' in the other strand, which is protected and restored by the enzyme

• Type II topoisomerases which concern both DNA strands allowing the passage of two twisted DNA strands through a protected and repaired 'hole' made in the two bound strands.

Type I topoisomerase

The following diagram explains their action:

	Type I topo-isomerase is bound at two adjacent spots on the same DNA strand.
	DNA is cut on one strand (red). The topoisomerase maintains the two sides of the cut free from any nuclease aggression.
	The 'blue' strand crosses the 'red' strand and the topoisomerase repairs the hole in the 'red' strand before leaving the DNA.

Type I Anti-topoisomerases

There are two drugs used in daily practice:

• Irinotecan (Campto™)
• Topotecan (Hycamtin™)

The action of type I anti-topoisomerases is to prevent the reconstitution of the cut DNA strand, thus inhibiting correct DNA synthesis.
These products are comparatively new, and have relatively high haematological toxicity (and also digestive when administered orally). Their genuine role in the therapeutic array is yet to be defined.

Anti-topoisomerases II  :

Type II topoisomerase

Type II topoisomerase binds to both DNA strands and allows the passage of a double strand through this 'hole' thus allowing DNA to unwind.
The following diagrams attempt to explain this process:

	Type II topoisomerase binds itself to two DNA strands.
	Type II topoisomerase successively opens the two strands to allow the passage of a double strand.
	Passage of the two DNA strands through Type II topoisomerase.
	Type II topoisomerase is liberated. The DNA has been untwisted.

Type II Anti-topoisomerases

This definititon encompasses two products:

• VP-16 or etoposide (Vepeside™ or Etopophos™ or Celltop™)

• VM 26 or teniposide (Vehem™ or Vumon™)

These two products are derived from podophyllotoxin from the mandrake plant.

VP-16 is one of the most frequently used chemotherapy products to treat cancer. Its main toxicity is haematological.
VM-26 is used for treating lymphoma.

The presence of a type II anti-topoisomerase results in the breaking of DNA strands since they cannot be attached again after the passage of the other double DNA strand.

	The anti-topoisomerase (grey oval element) does not prevent the usual binding of type II topoisomerase to DNA.
	After the passage of the double DNA strand , the anti-topoisomerase does not allow the attachment of the opened double strands, since it cannot be detached from the ends.

Intercalating agents:

The first available explanation on the action mechanism of intercalating agents was that since they were very flat, they could intercalate between the DNA strands and block their replication.

Many products are derived from the family of anthracyclins:


                            Generic formula of anthracyclines

doxorubicin (Adriamycin®, Rubex®),

daunorubicin (Daunorubicin ™),

epirubicin (Ellence™),

mitoxantrone (Novantrone™),

pirarubicin (Theprubicin™),

idarubicin (Idamycin ™)

actinomycine D (Dactinomycine™)

amsacrine (AMSA P-D™)

The following diagram explains the supposed action mechanism of such intercalating drugs.



Supposed action mechanism of intercalating drugs.

In reality, the real action mechanism of intercalating anticancer drugs is probably more closely related to a competition with type II topoisomerases.



Probable action mechanism of intercalating anticancer drugs: competition or type II topoisomerase fixation.

The first four drugs are members of the family of anthracyclins and are produced by fermentation.

As the above formula shows, they are made of a chromophore with 4 aromatic rings and of a sugar (daunosamine).

These products provoke three main common toxicities: dose related medullar aplasia, local toxicity if extravasation occurs and chronic cardiac insufficiency when high cumulative dosage has been administered.


Mitotic spindle poisons:

These products act during mitosis when chromosomes are split and begin to migrate along the tubules of the mitosis spindle towards one of its poles, before cell separation.

These substances are very similar but with somewhat varying toxicities and actions:

vinblastine (Velban *)

vincristine (Oncovin *),

vindesine (Eldisine *)

vinorelbine (Navelbine *).



Action mechanism of poisons of the cellular spindle. Under the action of such poisons, the spindle is disorganised with the dispersion of chromosomes during mitosis.

These molecules are highly active but should be administered strictly intravenously. Their major toxicity concerns blood count as well as the peripheral and intestinal nerves.

Taxanes:

The action mechanism of these products is different: they provoke bundles of microtubules and the stabilisation of cellular microtubules which are normally in equilibrium with soluble tubuline. Thus a great number of vital cell functions are disturbed: mitosis, maintenance of cell morphology, morphologic changes, neurone formation. The dividing cells are stopped at interphase G2-M.



Comparison of the action mechanisms of spindle poisons (such as periwinkle alkaloids) and taxanes. The former prevent the normal formation of ttubulin by adding tubulin through phospho-kinase. The latter prevent the liberation of the various tubuline elements which require the action of phosphatase.

Two drugs are now available:

paclitaxel (Taxol™ or Paxene™ )

docetaxel (Taxotère™)

Whereas their activities present great similarities, the toxicities of paclitaxel and docitaxel are somewhat different.

Both have a severe haematological toxicity essentially in the form of leukopenia. They both provoke complete hair loss.

Paclitaxel has slowly progressing neurological toxicity with allergic phenomena which can be prevented by pre-medication.

Docletaxel provokes the progressive, dose related appearance of persisting oedema (first limited to lower limbs). Pre-medication by corticosteroids reduces the incidence of this complication.


Goals of chemotherapy & Curative Chemotherapy

There are four different aims at prescribing cancer chemotherapy:

curative intent,

adjuvant intent,

palliative intent,

experimental intent.

Chemotherapy with curative intent

Chemotherapy is the main step in curing cancer (and generally follows another therapeutic modality). If chemotherapy is not correctly performed, the patient’s chances for recovery are considerably reduced.

The obvious consequence is the necessity to use the best protocol (i.e. the best chemotherapeutic association), with the best dosage (i.e. often the highest possible dosage) with the highest chance of curing the patient. As the above diagram shows, without chemotherapy, there is little chance of survival. We should always offer our patients the best chances of being cured.

Within this category, we should classify chemotherapy for:

leukaemia,

lymphoma,

testis cancer,

placental choriocarcinoma,

embryonic tumours of childhood,

osteosarcoma

neuroblastoma,

locally advanced ovarian carcinoma,

small cell lung cancer,

breast inflammatory cancer.

Due to the necessity to obtain a lasting, complete response, which is the only real way to offer long-term survival, we need to be prepared to assume our responsibility and to take risks for our patient; risks involving potential high toxicity, blood transfusion, prolonged hospitalisations and sterile rooms.

Adjuvant chemotherapy:

In this situation, chemotherapy is used because, statistically, patients receiving chemotherapy have a better chance of survival than patients without chemotherapy. However, this does not apply as a general rule since, for one given patient, the side effects of chemotherapy may annihilate its statistical positive effect.


Explanatory diagram of the aim of chemotherapy with an adjuvant intent

Thus, in this setting, it is not legitimate to take unreasonably high risks, in particular numerous and potentially lethal aplasia episodes or prolonged hospitalisations.
Adjuvant chemotherapy

It is prescribed after the main treatment modality.

With the addition of chemotherapy, the results of this major treatment (surgery or radiotherapy) are statistically improved.

What does the above diagram mean? 50% of patients are cured by the initial treatment, with or without chemotherapy. 40% cannot be cured by the initial treatment PLUS chemotherapy. Thus, the genuine benefit of adjuvant chemotherapy concerns only 10% of patients.

This small number explains current research on prognostic factors, proteomics and other characteristics which might determine the patients for whom chemotherapy is not necessary (the 50%) or for whom more intensive treatment might be justified due to the poor results obtained with standard treatment (the unfortunate 40%). Unfortunately, we are, as yet, unable to differentiate the various categories and must deliver adjuvant chemotherapy to all patients.

In this category of adjuvant chemotherapy, we can name:

breast cancer,

colo-rectal cancer,

bladder cancer,

head and neck cancer,(?)

cervix cancer(?).

Neoadjuvant chemotherapy

The aim of neoadjuvant chemotherapy is to reduce the size of the primitive tumour thus making it easier to operate. If chemotherapy is not efficient, the patient will require more extensive surgery.

For instance:

Neoadjuvant chemotherapy of a very extensive breast carcinoma may change the necessary surgery from mastectomy to lumpectomy

Neoadjuvant chemotherapy of urinary bladder cancer may, in association with radiotherapy, enable continued bladder retention.

For some authors, the results of neoadjuvant chemotherapy are not convincing enough to avoid radical surgery.


Palliative chemotherapy :

Palliative chemotherapy is aimed at prolonging survival and improving patient comfort.
Statistically, there is no, or very little improvement on survival.

The response rate is low (15-20%) or the duration of response is short (from a few months to a year). However, a few patients may benefit from a good response with a clear advantage in terms of survival, thus fully justifying such palliative chemotherapy. Others will not benefit from the treatment and will only suffer from its side effects.

Thus, a careful attitude should be adopted in order to analyse each toxic symptom and, if necessary, stop the treatment. The same caution should guide physicians when presenting such treatment to the patient or his/her family (always endeavouring not to give false hopes)..

Explanatory diagram of the aim of palliative chemotherapy

In this category of chemotherapy, can be treated:

• myeloid chronic leukaemia (although, with Gleevec, this is, in fact, no longer palliative chemotherapy),

• lymphocytic chronic leukaemia,

• myeloma

For these pathologies, although they are rarely definitively cured by chemotherapy, very long remission may be obtained with excellent quality of life. In these cases, if the word 'palliative' is stricto sensu correct, the increase in survival duration transforms this treatment into pseudo-curative chemotherapy.
Other palliative chemotherapy indications:

• metastatic breast cancer,

• soft tissue sarcoma,

• thyroid carcinoma,

• melanoma (?)..

For these latter palliative chemotherapies, one question should always be asked: is this chemotherapy of genuine benefit to the patient? If the benefit is low or if toxicity is high, then is it legitimate to continue this inefficient treatment, despite my personal desire to treat the patient and his/her desire to nourish hope through such treatment?

Palliative chemotherapy should not cover situations where patients and/or carers want 'to do something' and refuse to accept reality. In all cases, the physician should carefully monitor the efficiency and the toxicity and protect the patient from unnecessary side effects.

Experimental chemotherapy :


Other chemotherapies are, in fact, more or less experimental and should be administered in the strict respect of laws for protecting patients (in France, the Huriet Law):

• drafting of a protocol justifying the research,

• advice of an ethics committee,

• informed written consent from the patient,

• careful collection of all necessary data in order to report the progress or absence of progress.

This category of chemotherapies includes:

• lintracavity chemotherapy,

• intraarterial chemotherapy,

• intensive chemotherapy with autologous bone marrow transplantation (with the exception of a few pathologies for which this treatment has been clearly assessed),

• many associations of radiochemotherapy, yet to be assessed,

• any new treatment which is still in phase II or phase III trial stage before the publication of unequivocal results (and not a rapid, premature and unsatisfactory presentation).

Of course, treatment modalities for which the experimental results in well conducted studies are negative should not be prescribed even in 'experimental' situations or ”to continue to try do something for this poor patient”.

Principles of polychemotherapy :


More frequently than not, the use of only one anticancer drug is insufficient to obtain recovery or even a long-term clinical response. The rapid appearance of cancer cell resistance (cf. following pages) will result in treatment failure.

The simultaneous use of several drugs can offer an improved therapeutic index based on:

• the use of molecules with different action mechanisms;
  
• occasionally, a genuine synergy between drug families,
  
• furthermore, different toxicities which might allow an increase in dose intensity without proportionate increase in toxicity.

Increasing activity

Such increased activity is easy to demonstrate in vitro or in vivo in animal studies. In a clinical setting, randomised controlled studies are often necessary to objectively demonstrate the superiority of an association to the use of one solitary drug.

For instance, in ovarian carcinoma, it could be established that a higher response rate can be obtained by associating paclitaxel to cisplatin than by treating the patient with cisplatin alone.

New therapeutic associations are proposed based on previous experimental studies:

• Firstly, one drug is tested and proven to be active against a tumour: the drug is chosen because of its experimental in vitro or in vivo results using animals bearing experimental tumours or after systematically conducted Phase II studies.

• Drugs are then associated according to their action mechanisms which are presumed to provoke added or synergetic effect For instance, a topoisomerase inhibitor will be associated with an alkylating (classical association of VP-16 and cisplatin): thus the lesions induced by the alkylating drug (which are more important if it is a double strand alkylating agent) will not be repaired because of topoisomerase impairment. Thus, drug resistance could be avoided or at least delayed.

• Metabolic competitions between two drugs should also be avoided (for instance, there is no point in associating two alkylating agents),

• Similarly, drugs with cross resistance mechanisms (topic dealt with later), either spontaneously or after first-line chemotherapy, should not be combined.

Synchronisation and recruitment

Some cytotoxics (for instance mitotic spindle poison) specifically block the cell cycle of cancer cells (but also of normal cells) at a given time in the cycle. All cells then progress together towards the following cycle in a synchronous manner.

Thus, it should theoretically be possible to act with a second antimitotic phase dependent to which the cells are now more sensitive.

However, in daily practice, this synchronising effect is far less important than when observed in vitro or experimentally. Furthermore, synchronisation also affects healthy cells with an increased risk of excessive bone marrow toxicity.

Non addition of toxic effects

The combination of two drugs is also of interest if their toxicities are not cumulated (or only to a lesser extent):

• For instance we endeavour not to prescribe cytotoxic drugs with the same acute toxicity (for instance two highly emetic drugs or two neurotoxic drugs).
  
• We try to associate only slightly aplastic drugs (such as 5-FU or cisplatin) with more myelotoxic drugs (such as alkylating agents or anthracyclins).
  
• We try to avoid the simultaneous prescription of drugs with elimination metabolisms (thus avoiding two nephrotoxic products or requiring major hydration).
  
• The other drugs administered to the patient and whose combined toxicity might be increased (for instance nephrotoxic antibiotics and simultaneous cisplatin, modification of the metabolism of anticancer drugs by enzymatic inducers such as neuroleptic drugs, addition of ototoxicity of cisplatin and aminoside antibiotics).

Beneficial association

The benefit of polychemotherapy has been demonstrated for almost every type of cancer. Certain very well-known protocols are used on a daily basis.

Breast cancer	CMF (cyclophosphamide, methotrexate, 5-FU), FAC (5-Fluoro-Uracile, Adriamycin, cyclophosphamide), Epi-Tax (Epirubicine - Taxotere), AC : Adriamycine - Cyclophosphamide
Ovarian cancer	TC (taxol, cisplatin or carboplatin), CC (cyclophosphamide, cisplatin), CHAP (cyclophosphamide, hexaméthylmélamine, adriblastine, platine),
Testis cancer	BEP (bleomycin, etoposide, platin), EP (without bléomycine)
Lung cancer	EP (etoposide, platin), NP (navelbine, cisplatin)
Hodgkin's disease	MOPP (nitrogen mustard, oncovin, procarbazine, prednisolone), ABVD (adriamycin, bleomycine, vinblastine, dacarbazine)
Non Hodgkin's lymphoma	ACVBP (adrimyacin, cyclophosphamide, vindesine, bleomycin, prednisone), CHOP (cyclophosphamide, adriamycin, vindristine, prednisone)
Urinary bladder carcinoma	MVAC (methotrexate, vinblastine, adriamycin, cisplatin), Gemcitabine-CDDP

It can be noted that certain protocols have been elaborated more or less empirically and do not respect all of the 'rules' proposed above.

Haematological toxicity :


Cancer chemotherapy has numerous toxicities which can be classified in two major categories:

• acute toxicities, the great majority of which are common to many chemotherapy drugs,

• chronic toxicity, which, conversely, is often specific to one therapeutic family.

Haematological toxicity

Anaemia - Transfusions - Erythropoietin

Normal erythropoieis is the permanent, finely regulated production of red blood cells. Anaemia is commonly observed during malignancy without any connection to treatment. The mechanisms of this anaemia are diverse.

Most chemotherapies will eventually induce anaemia, generally of a normocytic type, sometimes macrocytic (for instance cisplatin), the correction of which can necessitate transfusions, particularly when anaemia becomes symptomatic (dyspnea, fatigue), which usually occurs when the haemoglobin level is lower than 8 g/dl.

Patients receiving aplastic chemotherapy, should be set on specific transfusion programs (in order to reduce the production of antibodies against irregular blood groups).

In reality, this very classical attitude is currently undergoing complete change thanks to the large use of erythropoietin. This hormone has become a genuine drug which should be prescribed when the haemoglobin level falls below 10 g / dl. This treatment avoids multiple transfusions, reduces respiratory disorders and alleviates the fatigue generally experienced by patients.

Thrombocytopenia and platelet transfusions

Some anticancer drugs are more severely toxic on platelets (dacarbazine, carboplatin). In general, after chemotherapy, the day that thrombocytopenia nadir will occur is well known, thus blood counts should be regularly performed in order to identify precisely when the patient will need to be transfused.

Simply speaking, over 50,000 platelets, there is no significant risk of haemorrhage (except in particular circumstances) and monitoring is sufficient.

Down to 20,000 platelets, among young and calm patients, rest and elementary precautions are sufficient to avoid any significant bleeding.

Below 20,000 (particularly among fragile patients), hospitalisation should be proposed in order to perform platelet transfusions after research for immunisation against HLA antibodies. Platelet concentrates, when the donor has the same blood group as the patient and the closest possible HLA group, induce a rapid increase in the platelet count; however this increase remains stable for a very short period (less than 48 hours) except when the patient's bone marrow takes over.

This attitude is very different to the one we adopt when faced with thrombocytopenia provoked by progressive medullar insufficiency (for instance due to marrow invasion by prostate cancer cells or breast cancer cells). Unfortunately, platelet transfusions are difficult to justify if no cancer treatment isavailable: in fact, it is just like a pierced barrel since the mean lifespan of transfused platelets is around 24 to 48 hours.

Platelets should only be transfused for acute thrombocytopenia.
We are still patiently awaiting the results of clinical studies validating a platelet growth factor.

Leucopoenia et antibiotics

Leukopenia is not in itself a major problem if it is of short duration. Any possible external or internal contamination should be avoided (visits, children, cleanliness and so on). There is no point in systematically instituting prophylactic antibiotherapy. (The opposite applies to very strong chemotherapies which require bone marrow graft or produce very long aplasia).

Conversely, the appearance of fever constitutes an emergency. It should generate the rapid verification of the white blood count and if leukopenia is confirmed, vigorous treatment should be instituted (possibly requiring rapid hospitalisation in order to avoid potentially lethal septic shocks). Some authors treat all cases of leukopenia (even with fever) at home if they last no longer than one or two days.

A chemotherapy protocol should precisely describe follow-up and in particular the days of the cycle on which white blood cell counts will probably fall to a nadir. On these specific days, precise haematological monitoring may be prescribed if necessary. This monitoring should be conducted by the physician prescribing the chemotherapy. Outwith this nadir period (and the day of prescription), blood counts are totally pointless.

Growth factors have brought significant progress in the treatment of leukopenia. Their indications are, however, much wider than the sole prevention of leukopenia.

Acute digestive toxicities :

Chemo-induced vomiting mechanisms:

Vomiting is a fundamental protective reflex mediated by the central nervous system to prevent the harmful consequences of ingested, potentially toxic substances.

The vomiting reflex is mediated by several distinct brainstem nuclei which integrate afferent inputs from diverse sources, including: the area postrema (a medullary site which contains the chemoreceptor trigger zone); the vestibular system; the pharynx and gastrointestinal and cardiovascular systems; and higher brainstem or cortical sites.

The peripheral afferent input from the gastrointestinal tract is mediated predominantly by the vagus nerve.
Afferent inputs to the vomiting centre are coordinated by the brainstem neuronal network of the dorsal vagal complex which includes the nucleus tractus solitarius (NTS). The NTS is a site for convergence of afferent input into the neuronal common efferent pathway, via the dorsal motor nucleus of the vagus, that produces the various visceral and skeletal muscular contractions necessary to produce oral expulsion of gastrointestinal contents, as well as changes in gut motility.

Many neurotransmitters have been implicated in the pathogenesis of vomiting, including dopamine, acetylcholine, histamine, opiates, serotonin and substance P. A more refined understanding of the relative importance of these neurotransmitters and their interrelationships in the regulation of vomiting is necessary for the development of more effective approaches for the treatment or prevention of vomiting.

Clinical aspects of chemotherapy induced vomiting

In addition to its continued importance as a clinical problem, vomiting induced by cancer chemotherapy may serve as an important model for understanding the physiology of vomiting in general.

Cisplatin is the single most emetogenic chemotherapeutic agent currently in use and may be considered the benchmark for evaluation of preventive strategies for CIV. At doses >50 mg/m² and in the absence of prophylactic therapy, cisplatin causes vomiting in virtually all patients. This vomiting typically follows a biphasic time course.

In the setting of clinical studies of cisplatin-induced emesis, chemotherapy induced vomiting has historically been described as occurring in two arbitrarily defined phases: the acute phase (from 0 to 24 h following the initiation of chemotherapy) and the delayed phase (from 24 h onwards).

Following initiation of the cisplatin infusion there is a latency period of 1–3 h before the onset of vomiting. The peak frequency of vomiting tends to occur at 6–8 h post-initiation of the cisplatin infusion, and this first phase of vomiting diminishes at approximately 12 h.

There follows a tendency for less emesis over approximately 4 h, after which the second phase of vomiting begins (approximately 16 h post-initiation of cisplatin). This second phase peaks between 24 and 72 h, although vomiting frequently occurs for several more days.

Many neurotransmitters exist which stimulate either directly or through other stimulation the chemoreceptor trigger zone (CTZ) situated in area postrema. During chemotherapy, most of the vomiting effect is produced by serotonin (5HT3) and Substance P (NK1). However, anticipatory vomiting also exist which might be related to stimulation of CTZ by other brain structures. The nucleus tractus solitarius (NTS) is the coordinator of the various visceral and skeletal muscular contractions necessary to vomit.

 
Role of serotonin:

The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) has been shown to be an important mediator of the early (‘‘acute’’) phase of CIV. Cisplatin causes a calcium-dependent exocytic release of serotonin from enterochromaffin cells in the gastrointestinal tract, possibly as a result of free radical generation. In patients receiving cisplatin, a large increase in the urinary output of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) is observed within 24 h, indicating the release of intracellular serotonin.

The released serotonin activates receptors on vagal afferent fibres, which stimulates the CNS centres that mediate the emetic response. 5-HT3 receptors have been shown to exist in the area postrema, nucleus tractis solitaris, subnucleus gelatinosus and in lower densities in the dorsal motor nucleus of the vagus and the spinal trigeminal tract.

These receptors are known to be of the 5-HT3 subtype, as 5-HT3 receptor antagonists (RAs) inhibit the acute emetic effect of cisplatin.

Although important in the acute phase, serotonin is not believed to be a significant mediator of emesis occurring more than 24 h after chemotherapy. Delayed CIV responds poorly to 5-HT3 antagonists, and it is therefore highly likely that other neurotransmitters are involved in the pathogenesis of delayed-phase symptoms.

Role of substance P

Substance P (Neurokinin 1 or NK1) is a member of the tachykinin family of neuropeptides. It is co-localised with serotonin in enterochromaffin cells in the gastrointestinal tract, and substance P levels in the peripheral circulation are elevated following cisplatin administration. Substance P crosses the blood-brain barrier, which raises the possibility that substance P of peripheral origin may act centrally to induce emesis.

Central nervous system penetration by the NK1 Receptor Anatagonitss has been shown to be essential for the prevention of vomiting in the first 4 hours following cisplatin-based chemotherapy, which suggests that the antiemetic effect these antagonists is mediated centrally, probably in region of the nucleus tractis solitaris.

A better effect is observed on delayed events (after 8 hours).

Plasticity of the emetogenic reflex

The effects of 5-HT3 antagonists are not simple to interprete even in experimental animal models. All patients do not react in a simlar way to antimetic treatments. These observations suggest that emetic reflex pathways may have some plasticity which should be further explored.

Acute vomiting

Vomiting is often present but is of varying intensity according to the chemotherapy drug, some being highly emetic such as cisplatin, dacarbazine or adriamycin.

Vomiting is one of patients’ major fears and is a frequent reason for stopping treatment.
The prevention of vomiting has been greatly improved with the arrival of the new antiemetic drugs which are 5-HT3 receptor antagonists: ondansetron, granisetron and tropisetron.

The study of chemotherapy induced vomiting shows that various components are involved in the process with varying kinetics: firstly, serotonine metabolites are involved, intestinal motility is then disturbed and finally cancer cell lysis with the appearance of necrotic substances in patient serum.
 When such treatment fails to give a positive result, neuroleptic drugs associated with corticosteroids can still be used, however they induce severe drowsiness, a situation which is not very comfortable for the patient if he/she needs to vomit.

The prevention of vomiting through such drugs should also avoid the occurrence of anticipated vomiting (patients vomiting before the administration of chemotherapy) and the constant anxiety at the prospect of returning to the day unit for chemotherapy, as well the occurrence of psychogenic vomiting.

The first cycle is the most important: everything possible effort should be made to prevent vomiting and even nausea. These drugs are sometimes so powerful that patients do not suffer any nausea at all. On the contrary, for a few patients, they seem to be totally inefficient and certain patients refuse further curative or adjuvant chemotherapy, when confronted with such painful situations.

Highly emetic chemotherapy	Moderately emetic chemotherapy	Slightly emetic chemohterapy
Cisplatin> 50 mg/m2 Cytoxan >1g /m2 Anthracycline > 50 mg/m2 Cariolysine Déticène	Cytoxan(<1g/m2) New Anthracyclines Cisplatin (< 50 mg/m2) Carboplatin Ifosfamide Taxanes Topotecan	Fluoro-Uracile Methotrexate Vepeside Oncovin Chloraminophene Purinethol Hydrea
Classification of chemotherapy drugs according to their emetic power

Delayed vomiting - Anorexia

Delayed vomiting is related to another relatively unknown mechanism which is different from acute vomiting and does not respond to new medicines. Delayed vomiting is generally more important if acute vomiting has been poorly controlled, but there is no absolute correlation.

Delayed vomiting is treated by metoclopramide, metoprimazine or alizapride in association with corticosteroids per os.

There is a new and very interesting class of drugs: anti-NK1 which act on neurokinin 1 (NK1) receptors and has a long-lasting emetic effect. Only one product is currently available: aprepitant (Emend™)

Delayed nausea is very unpleasant for patients and prevents the speedy return to a normal diet. Cooking smells are intolerable. Anorexia is very frequent, and is axacerbated when families force patients to rapidly return to normal eating habits (the general opinion being that a patient who doesn’t eat is very sick!). It is much healthier to ensure correct hydration than to fill the patient up with unwanted food.
With a three week cycle, it is most common to have only fluid diet during the first week, light food during the second and proper meals during the third. If the patient’s weight remains stable between the cycles, there is no particular risk. The physician should appease any family drama and reassure the relatives.

Mucitis

Certain anticancer drugs are specifically toxic for the mucosa: adriamycin, cytarabine, methotrexate. Preventive measures should be taken to avoid mouth pains and the dysphagia observed when mucosa abrasion occurs (see the chapter palliative care).

Various mouth washings may be prescribed: bicarbonate, amphotericin, xylocain, coca-cola. When the pain is too intense, mouth washings with morphine may also be prescribed.

Acute diarrhoea

Acute diarrhoea is frequent with certain anticancer drugs such as Tegafur and Capecitabine (in approximately half of patients).
 
Many other drugs may also induce such diarrhoea, but more rarely.
Occasionally, diarrhoea is so intense that rehydration is necessary.

Other early toxicity:

Anaphylactic shock

This rare complication essentially occurs with antitopoisomerase extracted from podophyllotoxin (VM 26 or VP 16). These products necessitate the presence of a nurse at the patient’s beside during the first minutes of infusion and of the physician in the near proximity in order to begin resuscitation if necessary.
Other drugs can provoke such shocks: paclitaxel, docetaxel, carboplatin, cisplatin. Therefore, a chemotherapy unit should always have the necessary resources for resuscitation.

Alopecia (hair loss)

Hair loss is quasi constant with products like VP 16, alkylating agents, anthracyclines, docetaxel, paclitaxel but rarer with cisplatin or carboplatin or 5-FU.

It is always a reversible process and the physician should speak frankly and simply about wearing a wig in order to dedramatise the subject with his/her patient. During the summer and at home, a cap (for men) or a light scarf are often very practical solutions to avoid permanently wearing a warm and unaccommodating wig.

Scalp hypothermia may be more or less efficient in maintaining hair. It uses a hat known as a ‘cold cap’ or a scalp cooling system which provides the constant cooling of the scalp. Its efficiency is related to the anticancer drug. The cooling cap should be used during the whole plasmatic passage of the chemotherapy.

Since the duration of this passage can be as long as two hours, such icy devices are not always tolerated and many patients will prefer to loose their hair than to suffer migraines due to the cold. For long metabolising drugs (of for high concentrations), the efficiency of scalp hypothermia is almost non existent.

Scalp hypothermia is theoretically contraindicated in the case of cranial bone metastases.
The loss of body hair including eyebrows, lashes, armpits and pubic hair should also be explained.

Acute renal insufficiency

It can occur particularly with the use of cisplatin or methotrexate.

For cisplatin, hyperhydration will avoid this insufficiency provided that it is sufficiently intense (at least 2 litres) and pursued after the platinum infusion. Thus, if the patient vomits, hyperhydration should be given intravenously.

High doses of methotrexate require alkalising urines and substantial hydration.

The tumour lysis syndrome may provoke renal insufficiency in relation to the precipitation of uric acid crystals in the tubules. Preventive hypouricemic drugs should be given as well as hyperhydration and urine alkalising.

Respiratory syndromes

They are rare complications but require urgent diagnosis.
Bleomycin, more rarely busulfan and 5-FU may provoke acute interstitial syndromes (such as allergy), necessitating strong and vigorous therapy by corticosteroids.

Extravasation

Extravasation is a fearsome complication which can induce extended and very painful skin necrosis.
This skin necrosis often necessitates large surgical excision with major delays or the permanent stopping of chemotherapy.

The observation of a poor venous skin network with porous veins should lead to the installation of an implantable venous device. We now have two types of device:

• those situated within the jugular vein or the supraclavicular vein, laid on the thoracic wall, they are of easy access for carers, but not always well tolerated by patients because they are not very aesthetic and sometimes damage clothes or are embarrassing when using a car seat belt.
  
• those situated near the brachiocephalic vein, which are generally more easily tolerated by patients, but their access may be more difficult for carers.

In any case, the installation of a venous device is a surgical intervention (day surgery or interventional radiology) which should be performed far from leukopenia (if possible just after surgery and prior to any chemotherapy), with the most rigorous aseptic measures. It remains a foreign body with the same risks of infection and phlebitis as other catheters.

Fatigue

Fatigue is a constant component of chemotherapy.
Certain chemotherapies are disabling for patients (to a greater extent if the patient is aged or with associated diseases or if the chemotherapy is very intense). The patient is obliged to stay in bed with mucitis and fever.

Conversely, adjuvant chemotherapy (or many curative chemotherapies), usually prescribed with a 3 week interval between cures, is far less tiring for the patient. Generally, during the first week after infusion, the patient can do very little (although a few do resume their normal activity as soon as they leave the chemotherapy unit). During the second week, energy is gradually restored and the third week is generally good.

Cures prescribed with a sufficient interval allow not only good haematological recovery but also a relatively good physical condition (especially for young patients).

As the cycles progress, the patient recovers needs more and more time to recover and is easily tired, especially if suffering from associated anaemia. Sometimes, fatigue is so intense that patients stay at home or in bed. It is wiser to stop treatment or at least to give a longer interval between the cycles thus enabling the patient to recover.

Chronic toxicities (1) :

Cardiac toxicity

Cardiac toxicity is most often related to anthracyclins (adriamycine) and has led to research for theoretically less cardiotoxic analogues (epirubicin, mitoxantrone).

During infusion, generally transitory electrocardiogram modifications can be observed (modifications of ST segment, repolarisation disorders, rhythm disorders).

Chronic cardiomyopathy is far more alarming and should lead to immediate stopping of anthracyclins. The risk becomes high with cumulative dosage over 500 mg/m2, or occasionally less according to age or previous radiotherapy or chemotherapy (cyclophosphamide).

Screening of such cardiomyopathy involves regular control of the ventricular ejection fraction.
Other anticancer drugs may be complicated by myocardial infarction but more rarely than those mentioned above (cyclophosphamide, 5-FU, cisplatin, methotrexate, VP 16).

Pulmonary complications

Pulmonary complications are not very frequent.

Bleomycin is responsible for the most dramatic accidents like chronic pulmonary fibrosis, which is frequent after a cumulative dosage of 300 mg/m² in adults ; a dose which should therefore never be prescribed. Prognosis is very gloomy.

Immunoallergic pneumopathy is a rarer form of pulmonary toxicity with devastating evolution.
Other anticancer drugs may have pulmonary toxicity: methotrexate (after a very long period of treatment) and misulban (after long treatment for chronic myeloid leukaemia).

Digestive complications

Constipation is frequent with Oncovin and rare with Eldisine or Vinorelbine. In fact, it is related to neurological toxicity on digestive nerves and can result in occlusive syndromes.

Toxic hepatitis is relatively frequent with elevation of hepatic enzymes (after belustine, aracytine), sometimes with cholostasis (purinethol, methotrexate). Mithracin may provoke small foci of hepatic necrosis which could be responsible for coagulation disorders.

Chronic toxicities (2) :

Skin and hair complications

Some anticancer drugs have toxic dermatological manifestations:

• Linear hyper-pigmentations and erythematous lesions of extremities and folds in relation with bleomycin,
  
• Pseudo-Addison hyperpigmentation of misulban,

• Nail alterations after Cyclophosphamide, 5-FU, Adriblastin, Taxotere,

• Photosensitisation of uncovered parts of the body (after methotrexate, 5-FU, Vinblastine, Adriamycin, Actinomycine D) or reactivation of cutaneous and mucous lesions induced by previous radiotherapy,

• 'Hand and Foot' syndrome provoked by 5-FU. (modification of the palms or soles)

Renal and bladder toxicity

Some agents have chronic renal toxicity:

• Cisplatin induces tubular necrosis (see the correction procedure in the description of Cisplatin)
  
• Conversely, carboplatin and oxaliplatin only have small renal toxicity,
  
• Methotrexate, when used with very high dosage, induces precipitation in the tubules (see the description of this product ).

In daily practice, with patients currently or previously treated by cisplatin, care should be taken when prescribing other nephrotoxic drugs (such as aminosides or anti-inflammatory drugs), since the tubular deterioration induced by cisplatin is irreversible.

Two agents can induce urinary bladder lesions with haemorrhaging cystitis: cyclophosphamide, but moreover ifosfamide which requires the systematic use of a urological protector (Mesna)

Chronic toxicities (3) :

Neurological complications

There are many different types of neurological complication:

• Peripheral neuropathies

  Related to Oncovin and other periwinkle alkaloids but also to cisplatin),
  They are expressed by tingling, deep sensory disorders, tendon reflex abolition. Motor weakness is rare.

• Evolution is slow and not always reversible despite vitamins, especially among aged patients,

• Treatment should be stopped at the onset of alarm symptoms.

• Cranial nerve paralysis

  (related Oncovin or cisplatin),
  They are more rarely observed, but there evolution is severe.

• Cisplatin induced ear toxicity

  Related to unitary and total dose, it has become one of this very powerful anticancer drug’s major toxicities.

• Medullary and meningeal syndromes

  Related to the intrathecal administration of methotrexate or cytosine arabinoside.

• Encephalitic syndromes

  They are rare but well documented for ifosfamide and cisplatin.

Gonad complications

• Among women

Alkylating agents and most polychemotherapy regimens provoke amenorrhoea, which appears earlier and is more likely to be irreversible if the patient is approaching menopause. When it does occur, patients suffer from all the usual difficulties observed during premature menopause.

 Some authors have proposed, when not contraindicated by the cancer pathology (breast carcinoma), systematic oestroprogestative treatment to avoid ovarian insufficiency.

Among patients who recover from amenorrhoea, pregnancies are possible without any particular risk of malformation.

• Among men

 Anticancer drugs block spermatogenesis and provoke sterility which can be irreversible.
Alkylating agents are the most toxic agents, especially during Hodgkin’s disease (using the MOPP protocol).

Therefore, sperm conservation should be systematically proposed before treatment, provided that the sperm is of good quality, which is not always the case during the initial acute phase of cancer.

If spermatogenesis recovers, the risk of congenital malformation is no higher than in men never having suffered from cancer.

Endocrine functions are well preserved (with normal sexual functions).

Secondary cancer risks

Secondary cancers are frequently observed after treatment with anticancer drugs and especially with alkylating agents, when used as monochemotherapy for a long period of time (misulban, alkeran).

The association of radiotherapy and chemotherapy in Hodgkin’s disease may induce a cumulative risk of 5 to 10% of secondary leukaemia. Such forms of leukaemia are announced by a preleukaemic syndrome. Faced with such a risk, prescriptions tend to be more intense but for a shorter period.

The chemotherapy protocol :


The chemotherapy protocol describes in detail the aim, the modalities, the complications and the expected results of the medical treatment which is going to be prescribed. It is used as a reference throughout the prescription.

Description of the prescription circumstances

The protocol precisely describes:

• the type of pathology for which it is prescribed (cancer location, histology),

• the cancer stage,

• its integration within a global multidisciplinary protocol,

• the clinical situations allowing or forbidding its use,

• other exceptional indications or contraindications,

• useful literature references.

Description of drugs

For each drug, the protocol precisely describes:

• the dosage (related to the weight, the body surface, the desired blood concentration, the desired Area under the Curve, and so on).

• the day, the hour, the order and the duration of drug administration,

• the route of administration,

• ,the adjuvant treatment (hydration, antiemetic drugs, antiallergic drugs, ...),

• the particular precautions that should be taken during the use of the drug and its follow-up,

Description of the chemotherapy cycles

The protocol then describes:

• the interval which separates the various cycles (or cures), thus defining the dose intensity

• the number of cycles, as programmed

• the main expected toxicities,

• the prerequisite conditions before beginning a new cycle (clinical recovery, biological recovery),

• the toxicities which necessitate complete stopping or delay in treatment,

• the preventive or curative measures that should be taken against these major toxicities,

• the treatment modifications according to the observed toxicity,

• the general rules of dosage adaptation.

Simplified diagram of a chemotherapy protocol

The clear, quality drafting and precise knowledge of the therapeutic protocol enable efficient treatment of 'borderline' patients:

low leukocyte count,,

low platelet count,

abnormal serum creatinine,

liver enzymes modification.

Generally speaking and for many protocols, in the case of abnormalities, the first step is to increase the interval between cycles (delay of one week before prescribing the next cycle in order to allow a return to a normal blood count). Sometimes, there are precise adaptation rules implying dose diminution of one drug. In general, if after two subsequent cycles, a delay was necessary, the dosage is lowered in order to maintain as satisfactory a rhythm as possible (at least as long as the therapeutic efficiency is certain). Sometimes, growth factors need to be prescribed in order to shorten a delay due solely to leucopoenia.

Preparation of chemotherapy :

Personnel

In dedicated health structures, two kinds of personal might prepare the chemotherapy:

• nurses,

• pharmacy personnel,

• or an association of both.

However, such preparation remains under the strict control of the pharmacist.

Centralised preparation unit

Such a unit is necessary when the number of weekly reconstitutions in a hospital reach one hundred and for every hospital or structure having a regional pivotal role in the treatment of cancer patients.
It should be a protected premises, free from any external contamination, airtight, overpressurised and easy to clean. The personnel should enter such premises in sterile clothing (overall, gloves, boots, mask, bonnet) and following surgical hand washing. These washing procedures should be repeated when they leave the premises.

The preparation hood, with an aspirating vertical flow, is equipped with a panel to protect the personnel
Other enclosure exist enabling improved drug monitoring and increased availability of personnel for other tasks.

All of these systems are intended to offer efficient protection of the personnel preparing the chemotherapy (it is known that without these precautions, chemotherapy traces would be found in their urine) and personnel would therefore be submitted to a high potential cancer risk induced by contamination.

The drugs and solvents necessary for the chemotherapy preparation are assembled together under the hood, thus enabling permanent control of prepared quantities. The personnel preparing the drugs should be allowed to work in the utmost calm in order to avoid technical or mathematical errors.

The preparation sheets and prescription book constitute further controls. The pharmacist is responsible for the perfect drafting of these documents.

Waste elimination is carried out in specific containers. It also permits a final precise control of the inflow of used drugs and the outflow of prepared solutions (by counting the empty packaging).

Preparation in the clinical ward

When such centralised units do not exist, a specific installation should be set up in each clinical ward.
The same hoods should be fitted, in a specific room, free from any cumbersome or unnecessary equipment or stores and with very little personnel disturbance.

The work place should be easy to decontaminate, chemically and bacteriologically.
In this room, it should be forbidden to drink, eat or smoke and prepare other injections. A specific refrigerator should be used for conservation.

The nurse should be allowed to prepare the solution in a calm setting in order to avoid dosage mistakes and protection errors.
However, such preparation in the clinical ward should be abandoned as soon as possible.

Chemotherapy administration :

Nurse personnel

The physician is answerable for the drafting of the prescription. All of the technical procedures are delegated to nursing personel who are responsible for their correct execution. To ensure excellent quality, sufficient numbers of competent nursing personnel (such as oncology nurses in many countries) specifically trained in the execution of chemotherapy treatment, is necessary.
In daily practice, knowledge of the action mechanisms and the potential dangers of anticancer drugs is vital for nursing staff and patients alike.

Nursing protocol

The elaboration of a nursing protocol, precisely describing how each treatment phase should be performed, with known risks and drawbacks, and procedures to correct them, is a necessary step in order to provide homogeneous treatment and to verify the perfect understanding of the prescription. Constant dialogue between the prescribing physician and the nursing team should prevent many complications.
A well structured nursing record, recording the different infusion times of each drug, the possible reactions and the patient’s psychological tolerance, facilitates continuous treatment follow-up and a posteriori controls. The precise knowledge of the observed toxicities (in particular digestive toxicity) enables adapted prevention. The regular and retrospective validation of all such clinical work tools guarantees their daily quality and efficiency.

Venous access

Quality venous access is always necessary to prevent extravasation accidents of products which are toxic for the subcutaneous tissue or muscles. When venous access becomes unreliable, the installation of an implantable venous access device is necessary and requires rigorous and regular monitoring.
This supplementary technical procedure should, in no manner whatsoever, be considered as banal, since it can involve rare complications. Rigorous indications should therefore be discussed with nursing staff. The psychological impact of such devises, which are often left in place after the end of chemotherapy, requires a clear explanation to patients by the physician, which should be reformulated by nursing staff.

Immediate treatment follow-up

The execution of the nursing protocol requires technical knowledge in order to prevent accidents (such as extravasation) during infusion as well as precise and adapted measures for each drug, prevention and treatment of rare acute accidents (anaphylactic shock, indisposition, allergic reactions, fever). Nursing staff should be able to react appropriately and efficiently before the physician is called to the patient’s bedside.

A precise protocol for post-therapeutic aplasia also constitutes a supplementary security measure. If it is correctly drafted, and with sufficient experience, a great deal of anxiety can be avoided for the patient and for the nurse.

In the same manner, the manipulation of continuous infusion pumps (for chemotherapy or morphine) requires regular daily practice in order to perfectly understand all of the potentially confusing alarms and to educate the patient on how to react.

Psychological aspects

Patient anxiety and anguish can often be prevented through a clear and complete explanation by the physician, but the reformulation of such explanations by nursing staff is far more important since many essential (at least for the patient) questions have not yet been asked (see section on psychology).

A composed technical execution and a reassuring and confident attitude on the part of the nurse are also important for the patient and his/her relatives. Patients can but be impressed by the calm self-confidence of carers.

Appropriate nursing experience also allows patient education on how to withstand chemotherapy: dietary advice to prevent or to limit vomiting and nausea, explanations on mouth washes to be carried out at home, preventive measures against diarrhoea or constipation or photosensitisation. More intimate discussions with patients can help them to understand the sexual disorders and the fatigue experienced by all chemotherapy patients: absence of libido during chemotherapy is neither abnormal nor uncommon.

A further clear and calm explanation should be made of haematological toxicity, of how to recognise it, and of some simple preventive measures against infection or bleeding. Practical knowledge should also be provided on the alarm symptoms that should prompt the patient to call his/her general practitioner, oncologist, or oncology nurse. All of these tasks are an essential part of the oncology nurse’s specific mission.

Patient questions largely extend beyond the technical aspects of chemotherapy and concern the whole
cancer process. Therefore, the care record (which is a shared document between physicians and nurses) should record the degree of information provided to the patient and also helps the physician to appreciate patient needs expressed between consultations.

Training in communication is necessary in order to prevent (or at least to attempt to prevent) the anxiety of nursing personnel and unintentional blunders which can be an important source of anxiety to patients.

Finally, although difficult to institute, questionnaires may be helpful (quality of life, feelings about treatment, etc.) to help the patient to express his/her feelings during treatment.

Chemotherapy follow-up  :

Description of the follow-up

The therapeutic protocol should describe the expected toxicities as well as the clinical and biological exams necessary for their detection and their treatment.

The prescription of these examinations and these adjuvant therapies is an essential part of chemotherapy prescription.

If closer follow-up is needed, the prescription should indicate the modalities of transmission of results (telephone, fax, e-mail) and any measures to be taken in order to enable the prescribing physician to react adequately and appropriately.

The quality of medical assistants is essential in this domain. If reassuring information is provided to the patient, it reduces the anxiety that may be generated by such intense follow-up.

Role of the general practitioner

The general practitioner should participate in patient follow-up and should be his/her confidant and advocate in discussions with the oncologist.

In view of numerous and continuous new developments, regular post-graduate training is necessary in order to up-date scientific and technical knowledge. A good understanding of new therapies and of their relevance, together with a mutually confident dialogue with the oncologist are essential to enable the general practitioner to entirely fulfill his/her role of a close at hand adviser to the patient.

Such improved general knowledge together with accurate and reciprocal information should avoid unnecessary blood tests, examinations and transport, and, conversely, should allow speedy and well adapted reactions when emergencies occur (fever, aplasia, haemorrhage, etc.).

The chemotherapy report :

The quality of the reports throughout the various treatment phases reflects the quality of the administered treatment. It allows the retrospective validation of treatment. The report should be written by the prescribing physician, the preparing pharmacist and the administering carer.

Initial report

The initial report describes the justification of the prescription, the protocol to be used, the general modalities required to conform to the protocol, the necessary follow-up, the expected results, the particular risks for the patient, the practical treatment modalities (hospitalisation, venous access, details of necessary follow-up).

 An illustrative diagram, possibly computerised, may help to give a clear and simple explanation to the entire team.

Specific information should be sent to the general practitioner, explaining the patient’s current situation and the expected benefits of the prescribed chemotherapy. A description of the protocol used, of necessary monitoring and of precisely what is expected of the general practitioner is the very basis of such information. Scientific and ethical justification of the future therapy should convince the general practitioner and thus, indirectly, the patient himself/herself.

The third part of this initial report concerns the information given to the patient.

Whilst the calm, oral explanation of treatment is necessary, this initial surge of bad news does not allow the patient to properly assimilate all of the information necessary for his/her confident cooperation.
Providing patients with an explanation booklet, setting up nursing consultations during which explanations can be reformulate and advice given, taking the time to explain once more, while performing the various preparatory acts (blood samples, venous device setting, and so on) are all extremely valuable complements to the initial information.

For certain experimental protocols, information given to the patient should be oral and then written via an explanatory document, and constitutes the first step necessary for obtaining the patient’s informed written consent.

Diagram of the various reports during chemotherapy treatment

Report for each cycle

The report should begin with the tolerance of previous cycles and should specify the important observations made during the clinical examination.

The biological examinations necessary for the prescription are then recorded and the dosage is calculated (first in unitary dosage, then total dosage). The expected specific side effects of this cure are detailed for the general practitioner as well as the date of the next cycle, if necessary.

This report is validated only after the administration of the chemotherapy.
In the case of an intercurrent incident (infection, local reaction, shock), this incident is reported and the actual administered dosage replaces or completes the prescribed dosage.

Report at the end of chemotherapy

This report resumes the patient’s clinical history during chemotherapy, counts the actual administered dosage and estimates the dose intensity of administered treatment.
Together with the clinical examination (and possibly scanners or RMI), it reiterates the initial therapeutic targets and the observed therapeutic result: complete response, partial response, stabilisation or, unfortunately, evolution under treatment.
The main toxicities are recorded (hospitalisations, dose modifications) using the usual WHO codification.

The report is then pursued throughout the following therapeutic phase: other chemotherapy, radiotherapy, laparotomy or simple follow-up.

Chemoresistance :

The efficiency of chemotherapy is limited by a resistance phenomena. The cancer cells possess or acquire the possibility to bypass the action mechanisms of chemotherapy drugs.
Some cancers are naturally chemoresistant to almost all drugs (for instance: kidney or thyroid cancers).

Others are initially sensitive, but develop resistance capacities during treatment. The drugs become less and less efficient with subsequent cycles. Many resistance phenomena are crossed among drugs: hence new drugs, as yet unadministered to this patient, are totally inefficient since the cancer cells have acquired protection.

Resistance mechanisms are the origin of primary or secondary chemotherapy failure. Although these mechanisms have been largely studied in vitro, the applications of such research remain uncertain.

Pharmacokinetic mechanisms

In order to be effective, the drug needs to reach the tumour in sufficient quantities. This depends:

• on its characteristics: absorption, distribution, metabolism, elimination,

• on the characteristics of the tumour or the organ:

  • very little access to non vascularised tumours,
  • sanctuary organs such as brain or testis.

• on individual characteristics related to
  • age,
  • sex,
  • weight,
  • renal and liver functions.
    
• on the adequacy between tumour kinetics and drug administration (phase dependent drugs should be delivered for prolonged periods of time).

Pharmacodynamic mechanisms

We can refer to many mechanisms:

Decrease in cellular input

Many drugs need a transport protein to penetrate cells: the loss of the transport protein’s activity leads to resistance against the drug.

Increase in cellular output

Many membrane transport proteins will expel the drug from the cell: glycoprotein P, protein MRP and LRP.

MDR or Multi-Drug Resistance

MDR explains the majority of primary and acquired resistance phenomena. It concerns drugs which are extracts from natural products such as anthracyclins, vinca alcaloids, taxanes, epidodophyllotoxin.
There is a cross resistance between all these drugs.

Glycoprotein P is the main transport molecule of these drugs and is coded by the MDR-1 gene. Certain tumours have spontaneously high levels of glycoprotein P, such as tumours of the colon, pancreas, kidney and hepatocarcinoma. Others initially express very low levels which increase, more or less rapidly, with treatment: tumours of the stomach, breast, ovary, lungs as well as sarcoma and lymphoma.

MDR is reversible in vitro: the transport of anticancer drugs is modified by a number of other drugs such as verapamil, quinine and certain experimental molecules: S-9788, PSC-833, GF-120418, VX-70.
The clinical applications to reverse MDR remain experimental.

Chemoresistance (2) :

Intracellular metabolism of drugs

Once inside the cell, the drug needs to be transformed in order to be active and then eliminated. The modification of such mechanisms will lead to cellular resistance.

Reduction of drug activation

• methotrexate : transformed by polyglutamation into a more active form

• fluorouracile: needs to be transformed into 5-FdUMP or 5-FTUP in ordert to be active (in relation to various enzymatic systems).

• cyclophosphamide: needs to be activated by cytochromes P-450 from liver cells,

• cytarabine: activated as ara CTP by deoxycytidine kinase

The reduction or the loss of activity of these enzymatic or metabolic systems lead to the appearance of resistance to chemotherapy.

Increase in non specific inactivation

Two systems are concerned :

• gluthatione
• metallothioneins

Increase of specific inactivation by enzymatic hyperactivity

• cytarabine inactivated by cytidine deaminase
• fluorouracile inactivated by dihydropyrimidine dehydrogenase
• bleomycin: inactivated by hydrolase
• cyclophosphamide: inactivated by aldehyde dehydrogenase

Alteration of the target

Quantitative alterations

• Increase in the target concentration: the intracytoplasmic level of the drug becomes insufficient to inhibit all of the targets

• Decrease in the target concentration: the decrease in the level of topoisomerase enzymes reduces the activity of their inhibitors.

Qualitative alterations

• Point gene mutations modify the target (observed for VP 16).

Increase in the reparation of DNA lesions

The abnormalities induced by the drug are repaired by exacerbated repair mechanisms (for instance: appearance of resistance against platinum).

Alterations of the apoptosis mechanisms

The cells escaping from apoptosis are able to divide and transmit the genetic abnormalities induced by chemotherapy: thus, progressively, the cells become more resistant and malignant.

This mechanism is relatively frequently observed in vitro and explains the resistance to cisplatin.

Clinical ways to bypass the resistance

Use of synergic drugs

This is the main reason behind the systematic prescription of polychemotherapy.

Dosage increase

By increasing the dosage, we hope to slow down the appearance of resistant clones.

• total dosage
• dose intensity (dose/m²/week).

Use of MDR reversing agents

Some drugs are now included in clinical trials.

Optimisation of the use of conventional chemotherapy

• Pharmacokinetic dose adaptation and chronochemotherapy,

• Direct injection within the tumour (in situ chemotherapy),

• Use of activity modulators (such as folinic acid)

Gene therapy

• Repair of deficient gene system (highly experimental! ).