In addition to surgery, chemotherapy and radiotherapy, other treatment modalities have been evaluated. The majority of these approaches have limited application; some are still in the early phases of evaluation whilst others are no longer recognized as being valuable adjuncts to standard therapies. A brief discussion of these approaches to cancer treatment follows but readers interested in these topics are advised to consult specialist texts for further information.
Other treatment modalities include:
• biological or immunotherapy
• electrochemotherapy (ECT)
• cryosurgery
• photodynamic therapy (PDT)
• hyperthermia
• laser therapy.
Biological or immunotherapy
Harnessing the power of the immune system to kill neoplastic cells has been an area of intense interest and research for a number of decades. The complexity of the immune system is still being unravelled and the networks by which it is regulated means that immunotherapy is still not considered a treatment option for the majority of patients with cancer; when it is, it is seen as part of a multimodality approach rather than as sole treatment.
The immune system consists of a number of effector cells – cytotoxic T cells, natural killer (NK) and lymphokine-activated killer (LAK) cells – that interact with themselves, antibodies and accessory cells (macrophages, dendritic cells) in response to stimulation. Additionally, the properties and behaviour of the tumour can influence the outcome of these immune responses. Tumour characteristics that influence the immune response include the histology, anatomy and magnitude of the tumour, the immunogenicity of tumour cells and their ability to produce immunosuppressive factors or recruit suppressor cells.
Approaches to biological therapy have included:
• non-specific stimulation of the immune system
• specific stimulation of the immune system.
Non-specific stimulation
Older studies evaluated a number of non-specific immunostimulants that included bacillus Calmette–Guérin, Corynebacterium parvum, levamisole and acemannan, and finally liposomal-muramyl tripeptide (L-MTP) to which a number of tumours showed some response.
Liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE)
L-MTP-PE is a non-specific activator of monocytes and macrophages. Without the liposomal coat MTP is rapidly removed from circulation so encapsulation allows adequate delivery to target sites and ensures that it remains localized for sufficient time to allow activation of effector cells.
The best-known application of L-MTP-PE in veterinary oncology was its combination with platinol-based chemotherapy in the management of canine osteosarcoma (Kurzman et al 1995, MacEwen et al 1989) and splenic haemangiosarcoma (Vail et al 1995). In all cases treated, L-MTP-PE was used in the adjuvant setting in combination with standard chemotherapy protocols. In one such report the median survival time for dogs treated with L-MTP-PE was 14.6 months compared to 10 months for dogs not receiving L-MTP-PE (Kurzman et al 1995). Unfortunately, in spite of the early promise, limited availability has restricted the use of L-MTP-PE in veterinary oncology.
Specific stimulation
This includes:
• lymphokines and monokines
• adoptive cellular therapy
• antibody therapy
• growth factors
• vaccines.
Lymphokines and monokines
Interferons alpha, beta and gamma (IFN-α, -β, -γ) form a class of small glycoproteins that have a number of biological activities in the body and were initially characterized for their production in response to viral infections.
IFNs have a number of effects on cells, including induction of apoptosis and inhibition of angiogenesis by inhibiting the proliferation of vascular endothelial cells and therefore potentially targeting the vasculature of tumours. IFNs increase the activity of NK cells and IFN-γ can activate cytolytic T lymphocytes. IFN-α has been used in infants with haemangioma and patients with Kaposi’s sarcoma. IFN-α also appears to have some activity against human melanoma, particularly in patients with stage II and III disease (Kirkwood et al 2001). Melanoma, as the most immunogenic of all solid tumours in humans, will preferentially lend itself to biological therapy and is the tumour against which vaccine therapy to stimulate the immune system has yielded the most exciting results (see below).
Human recombinant IFNs are available but as yet their efficacy in canine tumours has not been established. Human IFNs have been used in the management of cats with retroviral infections and in one early study feline leukaemia virus (FeLV)-positive cats given low-dose IFN-α (0.5 U) had increased survival times (500 days) compared to untreated cats (73 days) (Cummins et al 1988). The problem with using xenogeneic recombinant material is the development of neutralizing antibodies and recombinant feline IFN is now commercially available.
Interleukins
Interleukin-2 (IL-2) is a 15 kD glycoprotein secreted by activated helper T lymphocytes and has a number of regulatory functions. When certain populations of lymphocytes are exposed to IL-2 they acquire the capability of killing tumour cells. This activity is described as lymphokine-activated killer (LAK) cell activity. Liposome-encapsulated IL-2 has been used as an inhalant against pulmonary metastases.
Antibodies
The initial promise of using monoclonal antibodies (MAB) directed against tumour-associated antigens has not impacted on the management of veterinary patients. One MAB directed against antigens expressed on canine lymphoma cells (MAB 231) was developed in the early 1990s and became commercially available (Jeglum et al 1987).
Growth factors
Granulocyte–macrophage colony-stimulating factor (GM-CSF) promotes the growth and differentiation of neutrophils and cells of monocyte lineage. Administration of GM-CSF to patients increases the levels of circulating neutrophils, eosinophils, macrophages and lymphocytes. Recombinant human GM-CSF has a number of applications in human oncology, including the management of chemotherapy-induced neutropenia. The immunostimulatory function of GM-CSF is also being explored in vaccine production (see below).
Vaccines
The concept of anti-tumour vaccines is not new but with increasing technology a number of potential anti-tumour vaccines are currently being evaluated. Malignant melanoma is the most immunogenic of all solid tumours and is resistant to chemotherapy, making it an ideal tumour with which to explore the possibilities of developing biological means of attack. These include using autologous or allogeneic tumour cells genetically modified with DNA coding for GM-CSF (Hogge et al 1998). Other cancers under investigation for vaccine development include B-cell lymphoma, again involving genetically modified GM-CSF.
Currently, one melanoma vaccine developed in the USA has a conditional license for the treatment of canine patients (see Chapter 13).
Recently, U’Ren et al (2007) reported on the preliminary results of a vaccine directed against canine haemangiosarcoma cells.
Electrochemotherapy
Electrochemotherapy (ECT) combines the local or systemic administration of a chemotherapeutic agent with the application of electrical pulses to increase the uptake of drug by neoplastic cells. Drugs that have enhanced uptake include bleomycin and cisplatin. Results to date have been anecdotal (Spugini et al, 2006 and Spugini, Vincenzi, Betti, 2008).
Cryosurgery
Cryosurgery is the controlled destruction of unwanted tissue by the application of cold temperatures. Cooling temperature (–20°C) for 1 minute or longer destroys almost all unprotected mammalian cells (Mazur et al 1970, Walter 1970). In recent years it has become less popular because of the superior results and greater access to radiation and lasers.
Advantages
Cryosurgery is relatively safe (avoidance of risks of general anaesthesia) and rapid (Withrow et al 2007). The dimensions of freezing can be controlled with proper technique and equipment (Withrow 1980a) and there is no general systemic reaction. There is lack of haemorrhage (if no incision or ulceration) and minimum postoperative discomfort. Postoperative infection is rare (Fretz & Holmberg 1980). Freezing can be repeated without cumulative effects and can be used on tissue not readily treatable by conventional surgical techniques.
Disadvantages
The disadvantages of cryosurgery include limited indications, post-freezing odour and slough of necrotic tissue which may be severe when large areas are frozen (Krahwinkel 1980). The initial investment is relatively high and liquid nitrogen has a short storage life (Withrow et al 2007). Postoperative oedema may be life-threatening, e.g. oral cavity or pharynx. Some areas may be slow to heal, e.g. bone. Skin and hair may be depigmented (Withrow et al 2007). Scar tissue around areas such as the anus may cause strictures (Liska & Withrow 1978). Run-off cryogen can cause necrosis of normal tissues. Excessive freezing can destroy adjacent tissue whereas inadequate freezing will allow tumour recurrence. It is impossible to know with true certainty if adequate margins of frozen tissue have been achieved around malignant masses. Follow-up to monitor for local tumour recurrence is very important.
Indications
Cutaneous lesions
Cutaneous lesions include localized inflammatory and benign tumours. Treatment does not require a sterile field. Small, superficial, benign cutaneous and perianal tumours may be treated under sedation and local anaesthetic injected under the lesion, particularly if multiple lesions are present (Krahwinkel 1980). However, more extensive disease requires general anaesthesia. Tumours <2.5 cm are considered for cryosurgery. Larger tumours, especially aggressive tumours with life-threatening potential, are better treated surgically when possible (Withrow et al 2007).
• Perianal: small benign lesions are good candidates. In the management of perianal adenomas, cryosurgery has no advantage regarding rates of recurrence than other treatments (Holmberg 2003).
• Oral: small benign lesions are good candidates. Treatment of malignant lesions of the oral cavity with cryosurgery is expected to produce poor local disease control rates. However, cryosurgery may be used as palliative therapy for malignant oral tumours, e.g. geriatric patients where the client is unwilling to consider definitive treatment either by surgery or radiotherapy (Holmberg 2003).
Contraindications
Mast cells lysed by freezing release histamine and heparin locally. Local erythema and slough for the size of tumour may be excessive (Holmberg 2003), and rapid degranulation may induce hypotensive shock (Withrow et al 2007).
Tumours that have major bony involvement do not respond well and should not be treated by cryosurgery (Withrow 1980b) due to low water content of cortical bone and high vascularity of cancellous bone (Holmberg 2003). Freezing cortical bone kills cells and reduces strength by up to 70% (Gage et al 1966), so that spontaneous fracture is a continued risk months after treatment (Holmberg 2003). Liquid nitrogen vaporizes when sprayed directly onto cancellous bone.
Fatalities due to air embolization causing cardiac arrest (cancellous bone to venous sinus to right atrium) have been reported (Harvey 1978). Major blood vessels can be destroyed by necrosis and slough of surrounding tissues. Any large vessels within target tissues should be ligated beyond the limits of freezing to prevent haemorrhage when the eschar is shed (Holmberg 2003).
Photodynamic therapy
Photodynamic therapy (PDT) involves the administration of a substance known as a photosensitizer that, when activated by light of a specific wavelength, shows activity against neoplastic cells. Photosensitizers can be administered by a number of different routes (oral, intravenous, topical) and optimally they are selective for tumours (cells in S phase are the most sensitive). The limitation of PDT is that only superficial lesions can be treated; this is because, with systemic administration of a photosensitizer, the depth of penetration of the light is usually 1–1.5 cm, the actual depth depending on the wavelength. When the photosensitizer is administered topically the depth of penetration is even less (0.5 cm).
How does PDT work?
The photosensitizer converts light energy into chemical energy by interacting with other molecules whilst in an electrochemically active state. Two types of reaction are possible:
• Type 1: the excited photosensitizer reacts directly with other substrates to produce free radicals
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
