Other therapies for cancer

Many other therapies are used to treat cancer. Their utility is of great importance, in particular in offering patient comfort . They are curiously grouped together in this chapter although their action mechanisms and their modalities are very different. In the near future, some of these therapies will benefit from an individual chapter (for instance: targeted treatments).

Main therapies studied in this chapter

Diphosphonates are used for treating bone metastases

Classical immunotherapy

Passive non specific immunotherapy

Interferon
Interleukin

Non specific active immunotherapy

Intra-vesical instillations of BCG

Target treatment

What target specific treatments?

Monoclonal antibodies

Trastuzumab (Herceptin™)
Rituximab (Mabthera™ , Rituxan™ )
Alemtuzumab (Mabcampath™, Campath™)
Cetuximab (Erbitux™)

Active small molecules

STI-571 ou Imatinib mesylate (Glivec™, Gleevec™)
Gefitinib (Iressa™)
Erlotinib (Tarceva™)

Anti-angiogenic treatment

Bevacizumab (Avastin™)
Thalidomide

Anti-proteasome treatment

Bortezomib (Velcade™)

Other innovating drugs will sooner or later join this incomplete list over the following months or years. Some data may be incomplete. Thank you to my colleagues who may wish to offer suggestions or remarks.

Diphosphonates:


Most of the bone modifications observed during metastases (and especially osteolysis) appear to be related to stimulation of osteoclasts after interaction with cancer cells. Two main arguments are in favour of this cellular stimulation. Histological argument: there are almost always osteoclasts inside metastatic osteolysis zones. Most of the lacunae are of the size of osteoclasts and not of the adjacent tumour cells.

Therapeutic argument: all molecules which act on osteoclast bone resorption (in particular diphosphonate, gallium nitrate) are also excellent treatment for hypercalcemia induced by bone metastases.

Very many physiological and pathological mechanisms are implied during this stimulation.

Mechanisms of stimulation of the osteoclasts

Malignant osteolysis is the consequence of the osteoclastic hyperactivity in relation to their stimulation by various substances (with the old generic denomination of cytokine) which are produced by the tumour cells invading bone.
Osteolysis can be isolated (thus making osteolytic lesions in radiology) or accompanied by a osteoblastic reaction (making what is called osteodense lesions in radiology).

Mundy’s works showed that the main factors produced by the tumour cells were Interleukin 1 (or IL-1), Interleukine 6 (IL-6), tumour necrosis factors , the growth factor for T cells TGF-β, and small molecules related to parathormone (the normal hormone stimulating ostoclasts) called PTH-rP.

There exist a local self stimulation : IL-1 or TGF-β stimulate the secretion of PTH-rP by tumour cells and the osteolysis liberates growth factors TGF-β and IGF-1, which stimulate the malignant proliferation in situ.


Malignant osteolysis is the consequence of osteoclastic hyperactivity in relation to their stimulation by various substances (with the old generic denomination of cytokine) which are produced by tumour cells invading the bone.

Osteolysis can be isolated (thus promoting osteolytic lesions in radiology) or accompanied by an osteoblastic reaction (promoting what are known as osteodense lesions in radiology).

Mundy’s research demonstrated that the main factors produced by tumour cells are Interleukin 1 (or IL-1), Interleukin 6 (IL-6), tumour necrosis factors TNF-α and TNF-β, the TGF-β growth factor for T cells, and small molecules related to parathormone (normal hormone stimulating ostoclasts) called PTH-rP.

There is local self stimulation: IL-1 or TGF-β stimulate the secretion of PTH-rP by tumour cells and the osteolysis liberates growth factors TGF-β and IGF-1, which stimulate the malignant proliferation in situ.

Osteolysis is one of the factors provoking hypercalcaemia observed during cancer, in relation with the calcium liberated by uncontrolled hyperresorption of the metastasis.
 

Diphosphonates are synthetic analogues of endogenous pyrophosphate. The carbon atom replaces the oxygen atom and allows the fixation of two radicals which prevent the destruction of diphosphonates by the osteoclasts. The diphosphonates are bound to the bone hydoxyapatite crystals and block their growth and their dissolution.

Pyrophosphate	General diagram of diphosphonates

Marketing

Many disphosphates are available on the market:

• clodronate (Clastoban ™, Lytos™, Bonefos™, Ostac™),
  
• etidronate (Didronel™),
  
• ibandronate (Bondronat™, Boniva™),
  
• pamidronate (Aredia™),
  
• zoledronate (Zometa™).

Mechanism of action

Their mechanism of action is based on the inhibition of bone resorption by osteoclasts. They have a high affinity for mineralised bone and reduce the activity and the number of osteoclasts at the bone surface. They are metabolised in an analogue of ATP and thus disturb the mechanisms of osteoclasts. Moreover, recent products may also possess an activity on signal proteins (alteration of prenylation), thus inducing apoptosis.

When administered over a long period, they do not appear to have a negative influence on bone formation and mineralization, or on mechanical properties of the bone (they do have a very small influence on osteoblasts).

An alteration of the medullar micro-environment may also exist, in particular due to reduced angiogenesis, thus rendering tumour invasion more difficult. This may also explain the analgesic effect of such drugs. Other examples of direct action on tumour cells have been described in vitro, but involving high dosages and which are probably not clinically significant.

Indications

The main therapeutic indications of these drugs are:

• malignant hypercalcaemia,
  
• Paget's disease,
  
• Prevention of hypercalcaemia,
  
• Osteolytic manifestations of multiple myeloma,
  
• Prevention of osteolytic bone metastases.

In the last indication, diphosphonate might be able to reduce the number of pathological fractures which are so often observed in metastatic patients (for instance: breast cancer) and reduce the diffuse bone pains caused by dense bone metastases.

Interferon :


Interferon is a complex family of natural proteins induced in response to various stimuli by the host. The gene regulation of interferon synthesis may explain the various effects which are observed during viral, malignant and angiogenic diseases.

Interferon types

There are many types of interferon molecules:

Interferon type I (α, β, θ, ω ) is a family of products related to genes situated on chromosome 9. Their biological activity is very diverse: virus inhibition, reduced tumour proliferation, antigen modulation, immuno-modulation.

Interferon type II ( γ ) has other receptors and actions.

Antitumour activity

Interferon has been tested in many different malignant diseases for which some positive effects have been observed :

• Melanoma (increase of survival at high dosage),
  
• Kidney cancer (10 to 15% response rate),
  
• Myeloid chronic leukaemia (response rate in aproximatively 60% of chemoresistant forms),
  
• Kaposi's sarcoma associated with AIDS (with a lymphocyte CD4 level higher than 250/mm3),
  
• Hairy cell leukaemia (normalisation of biology).

It is difficult to explain by which mechanism an antitumour effect is observed among certain patients, since there are great heterogeneities between patients themselves, solid tumours generally being less sensitive than ‘liquid’ tumours.

Among the different mechanisms implied in the tumour response, the following are mentioned in literature:

• A direct effect on cell proliferation (modulation of STAT signaling),
  
• Enzyme induction, particularly for neopterin,
  
• Cell differentiation with modifications in reactions to growth factors,
  
• Modulation of antigen activities of the tumour surface antigen (particularly for melanoma),
  
• Stimulation of Natural Killer Cells, macrophages and dendritic cells,
  
• Stimulation of specific cytotoxic T lymphocytes,
  
• Stimulation of the production of antitumour immunoglobulins,
  
• Activation of other cytokines around the tumour cells (particularly Interleukine 2 or IL-2).

Toxic effects

Acute effects

 General acute effects are the most commonly observed manifestations: fever, shuddering, headache, muscle pains, nausea, vomiting, diarrhoea.

 Prolonged hyperthermia, tachycardia, anaemia, moderate neutropenia and/or rashes are also frequently observed.

More rarely observed: rhabdomyolysis, sub-acute liver necrosis.

Chronic side effects

 Certain of which are almost constant: anorexia, dysgueusia (perversion of taste), fatigue, depression.

Others are rare: weight loss, alopecia, hypothyroidism. And others very exceptional: nephrotic syndrome.

Recombining interferon

For oncology (at least in France) we can use Interferon α2-b with the following indications

• Hairy cell leukaemia,
  
• Asymptomatic evolutive Kaposi's sarcoma,
  
• Chronic Myelogenic leukaemia (in chronic phase),
  
• T Cell cutaneous lymphoma,
  
• Follicular Non Hodgkin's Lymphoma,
  
• Kidney cancer (advanced disease),
  
• Malignant melanoma (stage II),
  
• Multiple myeloma (after efficient chemotherapy).

The usual dosage varies according the pathology from 1 Million Units to 18 Millions Units, and is generally administered intramuscularly.

Interleukin 2 (IL-2) :

General considerations

Isolated in 1976, and known for its effects on activated T lymphocytes (hence the name T-Cell Growth Factor), Interleukin II is a cytokine synthesised by mononuclear blood cells.

It exerts numerous activities between the various populations of white blood cells (hence the name interleukin).

The development of a recombinant Interleukin II (Proleukin™), by genetic engineering, has allowed its use in human therapy.

Many studies have been performed in oncology, particularly in metastatic kidney cancer, for which we have almost no efficient therapy, but also for metastatic melanoma and various sarcomas, more or less insensitive to chemotherapy. Many of the initial promising and rapidly published results are nowadays debated.

In French pharmacopoeia, only the indication for metastatic kidney cancer remains.

Indications

Treatment of metastatic renal adenocarcinoma

It is generally acknowledged that patients should only be treated if they have no more than one or two poor prognosis factors, since only patients 'with good prognosis' (!) could possibly respond. These poor prognosis factors are:

- general status score >= 1, according to ECOG scale, 

- metastases in more than one organ, 

- an interval of less than 24 months between the initial diagnosis of primary tumour and the appearance of metastases.

Treatment administration

Many administration methods have been tested. The most frequent (since the best tolerated) is by subcutaneous injection. Very elaborate protocols have been set up, but generally a daily dose of 18 Million Units is recommended.

Objective response rates are between 15 and 30% (depending on publications), however, response is generally of short duration.

Complications

A the most frequently prescribed dosage

 In almost every patient and at every cure, the following are observed: fever, more or less pruriginous skin rashes, flu-like syndrome, nausea, vomiting, diarrhoea. Generally, systemic administration of paracetamol, antidiarrhoeic and antiemetic as well as antihistaminic drugs is instituted.

 The patient cannot work or undertake any significant daytime activity due to the flu-like syndrome.

More serious side effects have been observed:

There may be worsening of serous effusions, tendency to oedema with risk of general organic failure.

Due to this oedema, psychological disturbances are often observed with mental confusion, depression, light somnolence or coma. This treatment therefore has to be excluded in the case of brain metastases.
Worsening of previous bacterial infections may also occur.

A capillary loss syndrome has been described, particularly after intravenous infusion of the product. A loss of vascular tone is observed due to extravasation of plasma proteins and liquids in the extravascular space. General hypotension and organ hypoperfusion can be severe.

Doubts about the genuine indication

Due to these important side effects, in a pathology involving spontaneous rapid development, and due to the low number of truly enjoyable and lasting responses, many physicians doubt the genuine indications of Interleukin 2. The French Percy Quattro trial, presented by Dr Negrier et al at the 2005 ASCO meeting, demonstrated no benefit of Interleukin 2 (abstract LBA4511)

In an adjuvant setting, the German Cooperative Renal Carcinoma Chemo-Immunotherapy Trials Group (DGCIN) also recently published negative results.

Intravesical BCG :

Intravesical BCG constitutes a non-specific treatment of localised non- invasive bladder carcinoma. The precise mechanism of action is not known but is probably related to the bladder inflammation it induces which may reject the abnormal cancer cells from the bladder wall.

Main indications

Curative treatment of urothelial carcinoma in situ.
Prophylactic treatment of relapses from:

urothelial carcinoma limited to the mucosa,
urothelial carcinoma invading sub-epithelial connective tissue (pT1),
urothelial carcinoma in situ.

Administration

The treatment begins during the month after biopsy or transurethral resection, in the absence of any macroscopic urinary haemorrhage.

Induction treatment involves six weekly intravesical instillations, followed by consolidation treatment of one monthly instillation over 6 months.

A urethral catheter is installed in the bladder with the necessary surgical asepsis. After bladder drainage, a 50 ml suspension of BCG is slowly instilled by gravity, after which the catheter is removed. The patient must remain lying down for at least 15 minutes in supine position, on either side, or in prone position.

The patient can then stand up and can urinate the product after two hours.

Complications

Systemic reaction to BCG

This reaction is in the form of a generalised granulomatosis. BCG culture from the various affected organs is difficult and the pathology generally resembles a hypersensitivity inflammatory reaction. In this setting, allergic reaction arthritis may be observed.

Other manifestations can include higher fever (around 39°5 C) for a few hours, pneumonia, acute miliary BCG infection with hepatitis and cystitis.

The traumatic instillation with direct penetration into the general circulation promotes such septicaemia reactions. For this reason, an interval between resection and treatment, the absence of haemorrhage, the non traumatic set up of the urinary catheter and, for certain authors, the absence of prosthetic materials (such as hip, valve or pace-maker) require to be monitored.

When systemic manifestations occur and persist, certain authors institute antituberculosis treatment.

Urinary sphere complications

Intravesical administration of BCG may induce an inflammatory vesical response with fever, haematuria, pollakiura and transitory dysuria. This transitory phenomena is evidence that the inflammatory reaction has been attained in order to obtain the therapeutic benefit.

However, true urinary tract infections may occur, with bladder contracture, prostatitis, orchitis, epididymitis, ureteral obstruction or renal abscess. A small bladder syndrome may possibly be the consequence of these infectious reactions (very frequent micturitions due to a bladder capacity of less than 50 ml).

Systematic treatment might be necessary when stopping intravesical BCG treatment.

Silent progression towards infiltrating bladder carcinoma

Although not a genuine BCG complication, regular cystoscopies should be carried out after the end of treatment. Initially superficial bladder cancer can invade and infiltrate without any major cystocopic modification.

Targeted therapies (1) :


Great progress has been made over the last fifteen years on our knowledge of tumours and healthy tissues, in particular on regulating mechanisms for cell division and relationships within a multicellular organism.
Many transmission signals between cells have been elucidated, transmitting the order to multiply or to suicide or to differentiate when no cell division is necessary.

During cancer, these very subtle regulating mechanisms may be deregulated with some signal receptors being over-expressed, over-activated, other molecules being abnormal and permanently transmitting multiplication or death orders.

On the following diagram, the permanent need for constant small stimulation of breast cells by growth factors is represented.

A normal mammary cell [1] has, on its internal surface (close to the basal membrane), Epidermal Growth Factor receptors [2] which are represented as little yellow or red men. When the number of receptors is normal [3], the cell maintains a constant moderate activity in relation to the signals which are transmitted from the receptors to the nucleus. On cell [4], an over-expression of ErbB-2 receptors (in red) is observed, thus the smallest stimulation by a growth factor will induce uncontrolled cell multiplication. This is one of the mechanisms of cell disordered multiplication during cancer.

Most membrane receptors are transmembrane molecules. In the presence of their specific growth factor, the receptors will dimerise and this dimerisation induces a phosphorylation of intracell tyrosine kinases, thus initiating the signal transmission towards the nucleus. This is shown on the following diagram.

On this diagram, the growth factor (blue ball) can dimerise two adjacent receptors which may be slightly different, but are complementary (as generally observed in clinical situations). Dimerisation induces the activation of tyrosine-kinase (red balls with red rays). This activation is transmitted to proteins immediately adjacent to the cell membrane (such as the Ras protein).

Targeted therapies (2) :


These therapies are intended to block the action of growth factors, the activity of which is increased in many tumours. The following diagram explains the various techniques currently under exploration.

On this diagram of a tumour cell, a growth factor receptor is situated on the membrane cell (blue tulip). When it is activated by the growth factor, a signal is transmitted towards the nucleus and the transcription of the various proteins and enzymes necessary for cell division is initiated.

Four types of “weapon” can be developed:

1. An antireceptor antibody, bivalent, with the possibility of activating antibody dependent cytotoxicity.
   
   This is the mechanism of action of the therapeutic antibodies described later.
   
2. A vaccine can be elaborated (an antibody which becomes cytotoxic via fixation to the antigenic receptor).
   
   Such vaccines are now tested against melanoma cell membrane receptors.
   
3. An antireceptor antibody may be developed and coupled to a radioactive isotope (in order to produce specific metabolic radiotherapy) or coupled to a highly active cell poison (such as ricine).
   
   Such an association is now clinically tested with rituximab.
   
4. Small molecules which bind to the tyrosine kinases of the receptors and prevent their activation can be synthesised.

In any of these four situations, there is no signal transmitted from the membrane to the cell nucleus.
Each of these techniques has its advantages (specificity, sensitivity) but also its drawbacks (difficulty in penetrating through vessel walls, binding to serum proteins, destruction by various proteinases, stimulation of antibodies against antibody, etc.).

Antireceptor antibodies have benefited from monoclonal antibody techniques and hybridisation techniques between human and mouse immunoglobulins. The variant part of the antibody (specifically recognising the antigen) is developed from murine immunoglobulin, whilst the constant part is from human immunoglobulin. Thus, very few allergic reactions are observed and no antibody against (foreign species) antibody is produced (the renowned HAMA: Human Antibodies against Mouse Antigens).

Classical diagram of a hybrid antibody (also known as ‘humanised’): the purple area corresponds to the constant part of human immunoglobulin whilst the grey area corresponds to the variant part of a murine antibody, selectively elaborated through monoclonal antibody technology.

Trastuzumab:

Trastuzumab (Herceptin™) is one of the major developments in the treatment of breast cancer over recent years, but unfortunately only less than a quarter of patients can benefit from it.
There is an entire family of HER receptors.

The HER receptor family

The HER2 gene was discovered thanks to its homology with the gene coding for the epithelial growth factor receptor (EGF). It was therefore called Human Epidermal Growth Factor Receptor type 2 (or HER-2). The HER2 gene is also called c-erbB-2. It is also referred to as HER2/neu by certain investigators because of its similarities with the neu gene from the rat.
This HER2 gene is a protooncogen implied in the synthesis of a surface protein HER-2 which is a receptor with tyrosine kinase activity. It transmits growth signals from outside to inside the cell, thus participating in the regulation of cell growth, division and differentiation.

The overexpression of the HER-2 protein is found in many types of solid tumours and is induced by the amplification of the HER2 gene. This gene amplification results more or less from the deregulation of gene control rather than from a direct mutation of the HER2 gene. The overexpression of the HER2 receptor induces its constant activity which can then lead to malignant transformation.

The family of HER genes comprises 4 very close genes which code for growth factor receptors HER1 to HER4. All these receptors have a tyrosine kinase activity stimulating cell growth. This activity is essential in the regulation of cell growth and survival as well as cell differentiation and migration. The ligands for HER1 are EGF, TGF α, amphireguline, EGF bound to heparin, and probably others. Some ligands are known for HER3 and HER4 and appear to be related to the neu-reguline family (for nerve growth). There is no known ligand for HER2.

Each HER receptor exists as a monomer in equilibrium with dimers stabilised by the ligand. Even in the absence of known ligands, HER2 is the preferential partner for constituting heterodimers: HER2 is activated by the ligand recognised by the other partner receptor . Thus HER2 participates in signal transmission without any specific ligand.

In man, amplification of the HER2 gene is observed in many tumours and stimulates their growth. These tumours, which have an increased number of HER2 receptors on their cell surface, are called HER2 positive tumours. About 30% of breast cancers are HER2 positive, and many other solid tumours are also positive.
The presence of an amplification induced overexpression of HER2 receptors is a predictive factor of poor prognosis (reduction of disease free survival and of global survival).
The extracellular accessibility of HER2 receptors makes them a good target for antitumour treatment with monoclonal antibodies.

Composition

Trastuzumab is a mouse recombinant humanised monoclonal antibody IgG1. It reacts with HER2-Neu human growth factor receptors (ErbB2) which are overexpressed in breast cancer cells in approximately 20% of patients.

Overexpression of HER-2 is observed in 20 to 30% of primary breast tumours. Studies have shown that women with tumours overexpressing this receptor have a shorter survival than those with tumours which do not overexpress it.

Trastuzumab inhibits the proliferation of tumour cells overexpressing HER-2. Another mechanism of action is its major stimulation of antibody dependent cell cytotoxicity (ADCC).

Detection of the over-expression of HER-2

Trastuzumab should only be used among patients whose tumours overexpress HER-2. For other patients, the antibody is totally inefficient and can even be toxic for normal tissues.

The overexpression of HER-2 is detected by immunohistochemistry (IHC) on sections of fixed tumours. Patients who may benefit from Trastuzumab have an immunohistochemistry score of 3+ or a strong amplification as demonstrated by the FISH technique (Fluorescence In situ Hybridisation).

An increasing number of pathology laboratories are now producing reproducible and reliable immunohistochemistry results. Experts recommend an interpretation diagram in order to evaluate the intensity of the coloration of the membrane in relation to the increased number of receptors. If more than 10% of the cells are concerned, the slide should be classified as 3+.

Pharmacokinetics of trastuzumab

The plasma half-life of trastuzumab is around 28 days. This relatively long duration is explained by the ‘humanised’ nature of this antibody without immunogenic reaction. Thus, the recommended rhythm of injections is once every 3 weeks. The starting dose is 4 mg/kg, followed by a maintenance dose of around 2 mg/kg per week.

The response rate of patients overexpressing HER-2 is over 50%. The responses are long-lasting (several months to two to three years) in patients with cancers which are resistant to usual chemotherapy.

Indications

This product is only used among patients overexpressing HER2. Up to very recently, it was also only used in metastatic cancer.

As a single therapy, it is used for patients failing to respond to two different chemotherapy protocols, with at least one protocol containing anthracyclins and taxane.

Patients having received hormonal therapy, should be relapsing after this treatment modality.
In association with paclitaxel, in patients previously untreated by chemotherapy for their metastatic disease and for whom anthracyclin treatment cannot be instituted.

Numerous studies are currently in progress and will modify these indications in the following months or years.

Tolerance - Toxicity

In most patients, trastuzumab is remarkably well tolerated.

Some immediate hypersensitivity reactions may be observed: fever, dyspnoea, hypotension, rashes. Generally these reactions occur during the first infusion and do not recur afterwards, following simple antipyretic treatment.

More rarely, severe hypersensitivity reactions with shock, pulmonary oedema and severe cardiopulmonary insufficiency may be observed (among which, a few observations involving toxic death).
Cardiac toxicity has been observed in patients previously treated with anthracyclins. Cardiac function should therefore be evaluated before any treatment, and then regularly every 8 to 10 weeks. Cardiotonic treatment may be prescribed to correct this insufficiency if the therapeutic benefit of trastuzumab is impressive. Otherwise, trastuzumab should be stopped.

Rituximab : 

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody against the CD20 antigen, comprising the constant regions of human IgG1 and the variant regions of light and heavy chains of murine immunoglobulin.

Indication

It is active against malignant cells presenting antigen CD 20, i.e. in follicular lymphoma (stage III and IV), in aggressive diffuse large B cell non-Hodgkin’s lymphoma.
This treatment is a major step in the treatment of lymphoma.

Administration

Rituximab infusion should be administered intravenously, in hospital, under the strict control of a competent oncologist or haematologist, with all necessary rehabilitation resources close to the patient (at least for the first infusion).
 
Premedication including an analgesic drug (paracetamol), an antihistaminic drug (diphenhydramine) and corticosteroids should be systematically given before every infusion of rituximab.
One of the most feared side effects is the cytokine release syndrome (see below).

More commonly, reactions are less severe and spontaneously stop when the infusion flow is slowed down.

At the beginning of the infusion, the flow rate of rituximab should be around 50 mg/hour; after the first thirty minutes, the flow rate can be progressively increased by 50 mg/hour every 30 minutes up to a maximum of 400 mg/hour.

Cytokine release syndrome

Patients with major tumour mass or a high number of circulating malignant cells (>=25.000/ml) are the most exposed to the apparition of a severe cytokine release syndrome.

Its main characteristics are severe dyspnoea with bronchospasm and hypoxia associated with fever, shuddering, shaking, urticaria and angio-oedema. In the most severe cases, acute respiratory insufficiency can lead to death. This acute respiratory insufficiency is related to an interstitial pulmonary infiltrate or pulmonary oedema.

This syndrome usually appears during the first or second hour following the beginning of the first infusion.

For this reason, very precise monitoring should be implemented during this first infusion. The infusion should be stopped if any abnormality is observed, and drastic symptomatic treatment instituted.
This syndrome is observed in approximately 10% of first infusions although it is generally less dramatic.

Tumour lysis syndrome

The cytokine release syndrome can be followed by a tumour lysis syndrome (when very massive tumours are present).

This syndrome is characterised by a hyperuricaemia, hyperkaliemia, hypocalcaemia, increased LDH and acute renal insufficiency.

Therefore, rapid recovery from a cytokine release syndrome may be followed by a rapid deterioration.
The tumour lysis syndrome should be prevented using hypouricemic drugs and extensive hydration.
After such acute syndromes and their full recovery, patients treated again with a much slower flow rate, rarely experience further severe cytokine release.

Treatment responses

The response rates to rituximab in B cell follicular non-hodgkin’s lymphoma or in low grade lymphoma, relapsing or resisting to chemotherapy, are in the range of 50%. The responses are generally long-lasting.
However, many trials are currently in progress associating retuximab with classical chemotherapy regimens (like CHOP), and the indications of rituximab are changing with very encouraging results published each year.

Alemtuzumab  :


Alemtuzumab is a genetically engineered chimeric murine/human monoclonal antibody against the glycoprotein CD 52 situated at the surface of lymphocytes.

CD52 protein is usually expressed at the surface of normal and malignant peripheral blood B and T lymphocytes as well as monocytes, thymocytes and macrophages. The antigen is also slightly present (< 5%) on the granulocyte surface but not on erythrocytes or platelets.
Alemtuzumab does not perturb haematopoietic stem cells.

Alemtuzumab induces lymphocyte lysis by specifically linking to the glycoprotein CD52, via complement fixation and an antibody dependent cellular cytotoxicity

Indication.

The indication of alemtuzumab is chronic lymphocytic leukaemia which has become resistant to alkylating agents and fludarabine. However, in the near future, trials currently in progress will probably change its indications and possibly its administration.

Administration

Alemtuzimab should be administered intravenously, by slow infusion, in hospital, under the strict control of a competent oncologist or haematologist, with all necessary rehabilitation resources close to the patient (at least for the first infusion).
 
Premedication including an analgesic drug (paracetamol), an antihistaminic drug (diphenhydramine) and corticosteroids should systematically be given before every infusion of alemtuzimab.

The same cytokine release syndrome as for rituximab is feared and requires low initial dosing (3 mg on Day 1), followed by a very progressive increase (if well tolerated), 10 mg on Day 2, 30 mg on Day 3). The recommended dosage thereafter is 30 mg/day three times per week for periods of 12 weeks.
The beneficial effect of the treatment is observed before the 12th week.

The treatment is stopped when clinical symptoms recur or if it proves to be inefficient.

Cytokine release syndrome

It is a highly feared complication. (cf. rituximab)

Tumour lysis syndrome

It appears among patients with a very important tumour mass (cf. rituximab).

Other toxicities

Major lymphocyte depletion (which is the aim of the treatment) may have some consequences. It can last for weeks. The levels of CD4 and CD8 lymphocytes may require up to one year before being fully restored.

There is therefore is an increased risk of opportunistic infections which may require general prophylactic antibiotics (trimethoprime / sulfamethoxazole) and efficient antiherpetic treatment for up to two months. If severe infections occur, alemtuzumab should not be prescribed again.

Neutropaenia and thrombocytopaenia may be observed at the beginning of the treatment (although they have only minute levels of CD 52 on their cell surface).

Imatinib mesylate or Gleevec :

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is characterised by the expansion of tumour myeloid clones, which maintain their maturation ability. At the preterminal phase, the leukaemia cells loose this capacity and lead to acute highly chemoresistant leukaemia.

 A specific cytogenetic characteristic of such chronic leukaemia is the Philadelphia chromosome which is a reciprocal translocation between chromosomes 9 and 22 t(9;22)(q34;q11).

The molecular consequence of this translocation is the fusion of oncogen c-abl (Abelson mouse leukemia proto-oncogene) from chromosome 9 with sequences of chromosome 22 near to the breakpoint cluster region (or bcr). The new gene is called abl-bcr.

The C-abl gene codes for a tyrosine kinase more or less bound to receptors. Bcr-Abl tyrosine kinase activity is constitutively increased in CML cells, affecting numerous signal transduction pathways that are essential for leukaemic transformation, including increased cellular proliferation, antiapoptotic effects, and adhesion defects.

Imatinib mesylate or STI-571

As early as 1988, specific inhibitors of tyrosine kinases were discovered: 2-phenylaminopyrimidine can conduct to synthesis of new compounds which have been studied for their interaction with ATP receptors of tyrosine kinases (especially kinases from PDGF: platelet derived growth factor). STI-571 was shown to be a powerful and selective inhibitor of tyrosine kinase abl. In the absence of tyrosine kinase activation, no phosphorylation of the substrates implied in cell proliferation occurs and cell division is stopped.

Studies in Chronic Myeloid Leukaemia

Imatinib mesylate (Glivec or Gleevec™) is prescribed orally at a dosage of 400 to 600 mg. During the chronic phase, the remission rate is very high (up to 90%) with a complete clearance of the cytogenetic abnormality (Philadelphia Chromosome) in about 40% of these cases. This remission can last for long periods. If no response is observed with this dosage, a higher dosage may be used (up to 800 mg).

During the blastic transformation of Chronic Myeloid Leukaemia (where survival is generally around 3 months), approximately 50% of patients respond, 10% of whom have a complete cytogenetic response. Median survival is 8 months, but 30% of patients live longer than 15 months.

Other tumours

Some other tumours, for which tyrosine kinase activity is increased, might respond to this specific inhibitor.

Gastric intestinal stromal tumours (GIST) ) express a mutation of c-kit at their cell surface with a permanent stimulation of this proto-oncogene. They respond remarkably to Imatinib mesylate (about 60-70%) whereas classical chemotherapy is almost inefficient. Certain unresectable tumours have been known to completely disappear. However, unfortunately, most of these remissions are incomplete with relapse occurring after a few months. No specific immunohistochemistry has been found to predict tumour responsiveness.

Among other potentially sensitive tumours, small cell lung cancer, myelomonocytic leukaema and glioblastomas (which often bear an autocrine self stimulation to PGDF) are currently under study

Toxicity

The toxicity of Imatinib mesylate is low: nausea, diarrhoea, myalgias, periorbital oedema, various skin rashes.

Imatinib mesylate generally has minor medullar toxicity (except when treating the blastic crisis of CML). In this situation, intense leukopaenia may be observed: all of the granulocyte precursors bear the chromosomal abnormality and activation of tyrosine kinase, thus strongly reacting to the drug. Normal stem cells need a given time before reactivation.

When treating GIST, tumour necrosis may occur with massive gastric haemorrhage.

EGFR inhibitors :


Two molecules are now in clinical use.
ZD 1839 (Iressa™) and OSI-774 (Tarceva™) are selective inhibitors of the tyrosine kinase of the Epidermal Growth Factor Receptor. They block signal transduction and thus cell multiplication. They are administered orally.

Chemical formulae

Iressa is given orally at a common continuous dosage of 500 mg/m2	Tarceva is given at various dosages from 25 to 200 mg/day orally.

Detection of EGFR expression

The facility to detect the HER-2 receptor has enabled the development of a specific antibody (trastuzumab). However, to date, we cannot assay the overexpression of EGFR with a precise and reproducible method. Thus, it is difficult to predict which type of tumour and, within a given type which tumour, will respond to treatment.
Various methods were used:

local dosage of EGFR by analytical or immunoenzyme methods
   dosage of the serum protein,

fixation methods of EGF at the tumour surface,
transcription RNA level.

The expression of EGFR generally signifies poor prognosis with a poor response to chemotherapy.

Main indications

EGFR are very ubiquitous. EGFR abnormalities can be more severe than their overexpression would suggest.

In France, no such EGFR small molecule inhibitor has been accepted by the health authority and trials are still underway.

The main tumours for which these products seems to be interesting are :

• Non-small cell lung cancer, for which bright but generally short responses have been observed
  
• Hormone-independent prostate cancer
  
• Breast cancer, after failure of the usual treatment,
  
• Head and neck cancers,
  
• Rectocolic cancer,
  
• Ovarian carcinoma.

Main toxicities

Generally they are easy to monitor but may handicap the patient, since they are generally long term treatments:

• Diarrhoea (generally of low intensity), which may require treatment,
  
• Skin rashes which can involve the entire body
  
• Pseudo-acne of the face or the body, possibly infected,
  
• More rarely: headache, mucitis.
   
   Thalidomide :

  Historical context

  Thalidomide is an old drug. First used as an anxiolytic, it rapidly demonstrated major teratogenic effects (babies without limbs, other malformations). These malformations are due to a powerful negative effect on neovascularisation, which is necessary for normal foetal development. The idea to use this property in the antiangiogenic treatment of cancer emerged around ten years ago.
  One of the indications of thalidomide is leprous erythema nodosum, which is an immune reaction with vascularitis due to circulating immune complexes. The precise mechanism of this rare infection may involve the Tumour Necrosis Factor alpha (TNFα).
  
  Another indication is the treatment of very painful ulcers of the mouth, throat, vagina or rectum observed in AIDS or in Behcet syndrome. In such cases, involvement of Tumour Necrosis Factor alpha (TNFα) is also suspected.
  

  Structure of thalidomide which exists as two enaniomeres S(-) and R(+) and convert to each other physiologically.

  Indications

  At present, the only cancer indication (validated in France) is the treatment of resistant multiple myeloma.
  
  Given orally, the recommended dosage is around 200 mg/m2. Response can be spectacular with tumoral evolution stopped for long periods.
  

  Side effects

  Thalidomide may provoke severe peripheral neuropathies, beginning with bilateral, symmetrical, distal, sensitive disorders. Electroneurophysiological studies (sensitive action potential and motor-evoked potential) together with strict monitoring during treatment should prevent this severe complication.
  
  Due to the known teratogenic effects, the company heavily insists on the precautions to be taken to avoid any absorption by pregnant women. For the patient herself, such recommendations are superfluous since previous chemotherapies (and age!) prevent pregnancy.
  
  Other side effects include somnolence, vertigo, headaches, mood disorders.
  

  Other trials

  Other molecules, more or less related to thalidomide, are currently under experimentation. Certain new molecules may be more active and better tolerated than thalidomide, for instance in myeloma.
  
  Other tumours are also being studied, in particular hormone refractory prostate cancer.