strategies for managing cancer pain in dogs & cats part 2 ...€¦ · tumors, such as brain...

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Controlling cancer pain should always be part of a cancer treatment plan. Pain management should be implemented as soon as possible following diagnosis to address existing pain and prevent onset of new pain.

Even if the patient has no outward, objective clinical signs of pain, the practitioner should assume that any tumor has the potential to cause subclinical pain, and pain management should be considered as part of the therapeutic plan. This is an important concept in the veterinary profession because our patients are unable to communicate their level of pain directly.

TYPES OF CANCER PAINTumors can present in any part of the body, resulting in pain. In the fi rst article of this 2-part series, Pathophysiology & Assessment of Cancer Pain (May/June 2015; available at tvpjournal.com), we described 2 mechanisms for cancer pain: 1. Endogenous chemical irritation2. Direct tumor invasion with compression of normal

tissues. In addition, cancer pain can result from cancer

therapies, such as surgery, radiation therapy, and cytotoxic chemotherapy.

TYPES OF PAIN MANAGEMENTOptimal cancer pain management is determined by the type of cancer and the owner’s goals for treatment.

Broadly, 2 potential treatment pathways exist in veterinary oncology, both of which may employ analgesic drugs, radiation therapy, surgery, chemotherapy, or a combination of these modalities (Figure 1):

Strategies for Managing Cancer Pain in Dogs & Cats

PART 2: DEFINITIVE & PALLIATIVE MANAGEMENT OF CANCER PAIN Nicholas Rancilio, DVM, Diplomate ACVR (Radiation Oncology); Jeff Ko, DVM, MS, Diplomate ACVAA; and Christopher M. Fulkerson, DVM, MS, Diplomate ACVIM (Oncology)Purdue University

Welcome to Elements of Oncology—a column that addresses the many components of diagnosing, managing, treating, and monitoring veterinary cancer patients. This new column begins with a series of two articles that describe strategies for cancer pain management in dogs and cats, with an overall goal of raising awareness among the veterinary community about treating cancer pain early and recognizing that cancer pain can be considerably different from other types of acute or chronic pain.

FIGURE 1. Goal-oriented cancer treatment decision-making tree.

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• The goal in definitive treatment is long-term control of the cancer and potentially long-term, pain-free survival; iatrogenic pain is to be expected as a consequence of definitive treatment.

• The goal in palliative treatment is to relieve cancer pain and slow, or minimize, the rate of cancer progression. Table 1 (page 52) lists pain medications

discussed in this article, including dosing and frequency of administration.

ACUTE/IATROGENIC CANCER PAIN DUE TO DEFINITIVE TREATMENT As noted, iatrogenic pain induced by defi nitive-intent treatments is to be expected. However, the cost of iatrogenic pain in these patients is outweighed by the benefi t of longer-term survival. The pain management plan varies depending on the treatment modality used.

De� nitive SurgerySurgery is often used to treat localized cancer, and employed with defi nitive intent in a number of clinical scenarios, including: • Removal of tumors, such as low- to

intermediate-grade soft tissue sarcomas or mast cell tumors in which there is adequate room to remove a wide and deep margin (2 cm lateral + 1 fascial plane)

• Amputation of a limb to remove the anatomic

compartment encompassing the tumor (radical surgery).2-4 Pre- and intraoperative pain control for these

types of surgeries is similar to pain management used for orthopedic and soft tissue surgeries (eg, fracture repair, amputation due to traumatic injury). For example, the following medications are often administered:• Opioids and maropitant for anesthetic

premedication• Opioids (with or without ketamine), lidocaine,

and dexmedetomidine as intraoperative constant-rate infusions (CRIs)

• Opioids or local anesthetics for regional anesthesia techniques, such as nerve blocks. Postoperative pain management is also similar,

and frequently involves use of nonsteroidal anti-infl ammatory drugs (NSAIDs) and other analgesics, such as opioids.

Acute surgical pain management techniques have been reviewed extensively elsewhere and are not reviewed in detail here. However, see Consider This Case: Surgical Treatment of Osteosarcoma (page 50) for a case presentation that demonstrates the use of defi nitive surgery to treat osteosarcoma.

De� nitive RadiationDefi nitive-intent radiation therapy for residual local neoplastic disease is becoming increasingly common in veterinary medicine. This type of radiation therapy is: • Frequently indicated for treatment of

microscopic cancer left behind following first-attempt surgical excision of tumors, including soft tissue sarcomas and mast cell tumors

• Distinguished by the large size of the total dose delivered and the small size of the dose given at each treatment session (called a fraction). Treatment is typically delivered Monday through

Friday, with breaks on the weekend, for a total of

Use of Nerve BlocksIn humans, cancer pain management frequently includes nerve blocks, in which analgesic is injected into or around a nerve or into the spinal cord to block pain; nerves may also be transected surgically to relieve cancer pain.1 These modalities have not been used routinely in veterinary patients but may be worth exploring when other options are limited.

For more information on nerve blocks in dogs and cat, read Surgical Skills: Local Anesthesia for the Distal Extremity (September/October 2014), available at tvpjournal.com.

Use of Nerve Blocks

Recent studies have called into question the analgesic effectiveness of tramadol in dogs.5 Tramadol’s analgesic effect for acute/traumatic pain may be minimal due to lack of metabolic activation of the metabolite (M1) that is needed for mu agonism. In addition, the nonopioid mechanisms of tramadol, including inhibition of serotonin and norepinephrine reuptake, may or may not exist in dogs and

cats. Clinically, many cancer patients are geriatric and have comorbidities, such as renal disease, that preclude use of NSAIDs for mild to moderate pain. Therefore, options for at-home pain management are limited. Despite its shortcomings and questions about effi cacy, tramadol is widely used due to its convenience, safety, and perceived long duration of action.

Amputation of a limb to remove the anatomic

Tramadol: Effectiveness as a Pain Medication & Administration in Cancer Patients



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16 to 24 treatments, with fractions of 2 to 3 Gy, yielding a total dose of 48 to 60 Gy.

Levels of PainA general understanding of the type of pain induced by defi nitive radiation treatment is important; Table 2 (page 53) lists some common tumors treated with defi nitive radiation therapy and expected levels of pain associated with treatment.

In general, defi nitive treatment of deep-seated tumors, such as brain tumors, is associated with few painful side effects, whereas treatment of superfi cial tumors, such as those occurring on the skin or oral mucosa, is expected to elicit painful acute side effects. This difference in pain occurs because treatment of deeper tumors deposits most of the radiation energy in deeper tissues, such as the brain, while tissues and organs with more

sensitive pain receptors, such as skin, are spared from a signifi cant dose of radiation (paradoxically, the brain itself lacks pain receptors).9

The sensation of a headache or fatigue has been reported in humans with brain tumors, and the same sensation may occur in animals. This sensation is thought to be infl ammatory—a result of perilesional edema and potential stretching of the meninges due to the space-occupying mass.10

Acute EffectsThe target of radiation-induced damage is the DNA of rapidly proliferating cells, and the most signifi cant side effects of radiation therapy are desquamation of the skin, mucositis, and keratoconjunctivitis sicca of the ocular adnexa. These side effects generally occur in treated areas around a cutaneous, oral, or nasal tumor.

Acute side effects result from depletion of stem

Recently, a veterinary product with a higher concentration of buprenorphine (1.8 mg/mL; Simbadol, zoetisus.com) and a highly concentrated transdermal fentanyl liquid (50 mg/mL; Recuvyra, elancovet.com) have become available for treating pain in pets. Although these new, long duration, highly concentrated narcotics show promise, they must be administered and handled under the direct supervision of a veterinarian due to the potential for abuse and safety concerns.

Concentrated BuprenorphineOral transmucosal (OTM) buprenorphine at a dose of 80 to 120 mcg/kg (highly concentrated preparations, such as Simbadol, may make OTM administration more practical) is effective for analgesic durations of 12 to 24 hours in dogs and cats.6-7 We advise against sending this drug home with clients due to abuse concerns unless no other options are available for adequate pain control.

Transdermal FentanylTransdermal fentanyl liquid is a new method for treating acute pain in dogs (the product is not approved for use in cats and should not be used due to safety concerns). Its advantages include:• Efficacy: Appears to reach bloodstream within

30 minutes of application, attain therapeutic plasma concentrations within 2 to 4 hours of administration, and maintain therapeutic effect for 4 days

• Safety: See below• Economy: Less expensive than fentanyl

patches and injectable fentanyl• Convenience of administration: One

transdermal application provides 4 days of analgesia. The side effects of transdermal fentanyl

liquid are similar to those of injectable fentanyl, including anorexia, sedation, hypothermia, and dysphoria. Our clinical experience suggests that respiratory depression and bradycardia are less frequent than with injectable fentanyl. Remember that once transdermal fentanyl liquid has been applied, its activity cannot be halted unless it is antagonized partially or completely using butorphanol or naloxone, respectively.

To minimize risks when using transdermal fentanyl liquid as a premedication, other tranquilizers and sedatives should be avoided or administered at lower doses. Transdermal fentanyl liquid also has a propofol and inhalant sparing effect8 that should be considered during anesthesia induction and maintenance. For debilitated dogs, ½ to ¾ of the labelled dose may be applied rather than the full dose (2.7 mg/kg). Other opioids may be added if pain is under controlled.

Hospital personnel and owners should be aware of the site of administration of transdermal fentanyl and avoid direct contact with it for 72 hours after application. Any contact with bare skin should be avoided and hand washing should be implemented should anyone touch the area of application before 72 hours.

New Opioids for Pain Control in Cancer Patients



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An 8-year-old, castrated male golden retriever presented for evaluation of a mass on the distal femur. Non–weight-bearing lameness was present and localized to the distal femur. Complete blood count and serum biochemical profi le were within normal limits. However, craniocaudal and lateral radiographs revealed a moth-eaten-appearing, lytic region within the distal right femoral metaphysis (Figure 2).

1. PremedicationTwo hours prior to surgery: • Transdermal fentanyl liquid (2.7 mg/kg)

was applied to the dorsal scapular area; the dog demonstrated mild sedation 2 hours later.

• Further premedication was achieved with acepromazine (0.01 mg/kg IM), with no other opioids needed to facilitate IV catheter placement.

2. Anesthetic InductionAnesthesia was: • Induced with propofol (1 mg/kg

IV), demonstrating a noticeable propofol-sparing effect due to transdermal fentanyl and acepromazine premedication, and followed by oral tracheal intubation

• Maintained with isofl urane in oxygen with a circle breathing circuit.

3. Intraoperative Pain ControlAfter IV induction, but before surgical incision, an epidural was administered using bupivacaine (0.5 mg/kg) with sterile saline. A coxofemoral disarticulation was then performed.

Intraoperatively: • Ketamine (0.5 mg/kg bolus injection

followed by 1–2 mcg/kg/min IV CRI) and lidocaine (2 mg/kg IV bolus injection followed by 5–10 mcg/kg/min IV CRI) in crystalloid fl uid were administered.

• Dexmedetomidine diluted in physiologic saline at 0.5 mcg/kg/H was administered as an IV CRI.

• Two lidocaine patches (5%) were applied to the surgical site after skin closure.

4. Postoperative Pain ControlThe ketamine/lidocaine and dexmedeto-midine CRIs were continued for 6 hours postoperatively. The preoperative trans-dermal fentanyl liquid, which yields 4 days

of continuous analgesia, provided addi-tional pain control.

The patient was ambulating, eating, and drinking normally a day after surgery, and was sent home with:• Carprofen (4 mg/kg PO Q 24 H) and

tramadol (5–10 mg/kg PO Q 8–12 H) for breakthrough pain

• Gabapentin (10 mg/kg PO Q 12 H) for potential neuropathic pain.If pain is not controlled with the above

medications, consider other opioids, such as OTM administration of buprenorphine (120 mcg/kg Q 24 H).

5. Further Defi nitive TreatmentThe dog was treated with chemotherapy (carboplatin, 300 mg/m2 IV Q 21 days for 4 treatments) beginning 10 days after skin sutures were removed. Five months after completion of carboplatin, thoracic radiographs revealed pulmonary nodules consistent with metastatic disease. The patient began doxorubicin chemotherapy and is currently undergoing treatment.

FIGURE 2. Right lateral radiograph of the stifl e showing an aggressive, bony lesion in the distal femur. Note the area of focal bony lysis at the distal femoral metaphysis that has a moth-eaten appearance (*). Following amputation, the histologic diagnosis was fi broblastic osteosarcoma.

Consider This Case: Surgical Treatment of Osteosarcoma



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cells (such as keratinocytic stem cells in the skin) due to radiation damage. As radiation therapy progresses (usually 2 weeks into treatment course), acute side effects begin to appear as mild redness and dry, fl aky skin in the treated area, which results from the inability of stem cells to adequately repopulate the keratinocytes that have naturally progressed through their life cycles and shed.11 As treatment and time continue, these effects become more severe (Figure 3).

Acute side effects due to radiation are best managed proactively, with the knowledge that, although they may appear severe, their occurrence is transient and self-limiting. Cats are generally more resistant to acute side effects than dogs (Figure 4), and their side effects and discomfort tend to be less severe.

Late EffectsDeeper-seated tissues, such as muscle, nerve, and bone, are slowly proliferating in adult animals, and the effects of radiation therapy on these tissues may not appear for many years after treatment, if at all. These late effects of radiation therapy, like acute effects, are expected to occur only in the area of normal tissue near the treated tumor. If the smallest area of normal tissue possible is irradiated with small fraction sizes, the potential for late side effects in these tissues is less than 5%.12-13

Clinical evidence of late effects includes fi brosis, stricture, necrosis and, potentially, a second cancer in the organs surrounding the irradiated area. Clinically signifi cant late effects are irreversible and potentially life threatening, depending on their locations.

FIGURE 3. Moist desquamation after canine patient received 19 fractions of defi nitive radiation therapy for soft tissue sarcoma, excised with “dirty” margins from the distal forelimb. The limb is swollen, and several focal areas of redness and edema can be seen (A). One week after completion of defi nitive radiation therapy, the reaction has become more severe, with radiating redness, edema, crusting, and serum seepage (B). Two weeks after completion, note the near-complete resolution of moist desquamation; the skin is pink and smooth with a few areas of crusts and redness (C). Four weeks after completion, clinical signs have resolved completely (D).

FIGURE 4. Cat that has completed fraction 20/20 of defi nitive radiation therapy for a vaccine- associated sarcoma on the left paralumbar-fl ank region; dry, fl aky skin is present with mild redness (A). Same cat 1 week after fi nishing defi nitive radiation therapy; note that dry, fl aky redness has progressed and additional alopecia is present. No confl uent moist desquamation is present as in the dog in Figure 3 (B). Same cat approximately 2 weeks after fi nishing defi nitive radiation therapy; lesions have healed and hair is beginning to grow back (C). This patient was prescribed OTM buprenorphine (80 mcg/kg), as needed.

A B C D

A B C



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TABLE 1. Analgesic Agents & Other Nonpharmaceutical Techniques Commonly Used for Cancer Pain Managementa

PAIN CATEGORY APPROPRIATE ANALGESICS DOSE

Mild NSAIDsb

Carprofen (dogs only) 4.4 mg/kg PO or SC Q 24 H or 2 mg/kg PO or SC Q 12 HDeracoxib (dogs only) 3–4 mg/kg PO Q 24 H Firocoxib (dogs only) 5 mg/kg PO Q 24 HMeloxicam Dogs: 0.2 mg/kg PO, SC, or IV Q 12 H

Cats: 0.1 mg/kg PO Q 24 H every 2–4 daysPiroxicam Dogs: 0.3 mg/kg PO Q 24 H

Cats: Up to 0.3 mg/kg PO Q 24 HRobenacoxib (cats only) 1 mg/kg PO Q 24 HSteroidsb

Prednisone 0.5–1 mg/kg PO Q 24 H; taper to lowest dose that controls clinical signs

Prednisolone (cats only) 0.5–1 mg/kg PO Q 24 H; taper to lowest dose that controls clinical signs

Opioids

Tramadol (dogs only) 5–10 mg/kg PO Q 8–12 H

Moderate Opioids

Codeine 1–2 mg/kg PO Q 8–12 HHydrocodone 0.5 mg/kg PO Q 8–12 HMorphine 0.5–2 mg/kg PO Q 6–8 HHydromorphone 0.2–0.4 mg/kg PO Q 8–12 HBuprenorphinec Dogs: 80–120 mcg/kg OTM Q 12–24 H

Cats: 80–240 mcg/kg OTM Q 12–24 HTransdermal fentanyl patch 25, 50, 75, or 100 mcg/H patchTransdermal fentanyl liquid (dogs only) 1.3 mg/kg Q 4–7 days on dorsal scapular area

Severe Opioidsd

Morphine (dogs and cats) Same as aboveHydromorphone Same as aboveBuprenorphine Same as aboveTransdermal fentanyl patch Same as aboveTransdermal fentanyl liquid (dogs only) 2.7 mg/kg Q 4–7 days on dorsal scapular area

Can be combined with any other analgesics in different pain categories

Adjuvants

Amantadine 2–5 mg/kg PO Q 12 H Gabapentin 5–10 mg/kg PO Q 8–12 HOxcarbazepine 30–60 mg/kg PO 8–24 H Amitriptyline 1–5 mg/kg PO Q 12–24 HLidocaine patches 1–3 patches depending on size of wound and size of animal,

1 application on the superfi cial painful site for 5–7 days

Can be combined with analgesic agents in different pain categories

Nonpharmaceutical Modalities

Acupuncture

Physical rehabilitation

Nutraceutical and nutritional supplemental therapies

a. Modalities are appropriate for dogs and cats unless otherwise speci� ed.b. Do not administer NSAIDs and corticosteroids concurrently; only administer one NSAID at a time, and provide an appropriate washout

period (approximately 5–7 days) when switching from one NSAID to another or to a corticosteroid (and vice versa). Use with caution in cats.c. Highly concentrated formulations, such as Simbadol (zoetisus.com), may be used to help make the volume administered more manageable;

however, these products should not be sent home with clients due to safety and abuse concerns unless no other options are available for adequate pain control.

d. Combine the opioids with an NSAID and adjuvants for treating severe pain.



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TABLE 2. Anatomic Tumor Location, Side Effects, & Expected Pain Scores Associated with Defi nitive Radiation Therapy in Dogs & CatsANATOMIC LOCATION

COMMON TUMOR TYPES

EXPECTED SIDE EFFECTS OF RADIATION THERAPY

EXPECTED PAIN SCOREa

POTENTIAL DRUG INTERVENTIONSb

Brain MeningiomaGliomaPituitary

macroadenoma

Minimal, if any; many human patients report the sensation of a headache

0–3 (pain diffi cult to detect)

Prednisone Tramadol GabapentinBuprenorphine

Head/neck Squamous cell carcinoma

Oral fi brosarcoma

Mucositis, dry mouth, halitosis and, potentially, moist desquamation (skin of face)

7–10 NSAIDsTramadolGabapentin Amantadine OTM buprenorphineOral hydrocodone, hydro-

morphone, or morphine

Nasal Nasal adenocarcinoma (60% dogs)

Sarcoma (40% dogs)Lymphoma (most

common nasal tumor in cats)

*Acute side effects in cats tend to be less severe than in dogs

Depends heavily on treatment technique employed: pain may range from minimal to nonexistent (modern techniques) to severe desquamation (traditional techniques)

7–10 (traditional radiotherapy)

0–3 (advanced conformal radiation therapy)

NSAIDsTramadolGabapentinAmantadine OTM buprenorphine Oral hydrocodone,

hydromorphone, or morphine

Transdermal fentanyl liquid

Skin/subcutis

Soft tissue sarcoma Mast cell tumor Vaccine-associated

sarcoma (cats)*Acute side effects in

cats tend to be less severe than in dogs

Moist desquamation and sloughing of pads on digits (depending on location treated)

7–10 NSAIDs Tramadol GabapentinAmantadineOTM buprenorphine Oral hydrocodone,


Transdermal fentanyl liquid

Perianal/pelvis

Anal sac adenocarcinoma

Transitional cell carcinoma

Depends on treatment site but can range from mild to moderate stranguria/hematuria to diarrhea and severe moist desquamation of perianal skin

7–10 NSAIDs TramadolGabapentinOTM buprenorphineOral hydrocodone,


Transdermal fentanyl liquida. Pain scores: 0 = no pain; 10 = worst pain possibleb. Drugs listed are given concurrently; clinical signs of acute side effects do not occur until approximately 2 weeks into the

course of treatment and are not at their peak until 1 week after completion of treatment. Therefore, drugs are added sequen-tially as needed as clinical signs progress.

Treating Side EffectsThree general principles apply when treating acute side effects of radiation: 1. Administer pain medication2. Restrict activity until lesions have healed 3. Prevent self-trauma.

It is important to counsel owners that lesions will heal if these recommendations are followed.

First-line treatment for acute side effects is administration of an NSAID, such as carprofen (4 mg/kg PO Q 24 H, given with a meal). In cats,

acute side effects in rapidly proliferating normal tissues, such as the skin, are not as severe as those seen in dogs (Figure 3). Recently, a new NSAID for cats, robenacoxib, has become available in both injectable and oral tablet formulations. Robenacoxib is labeled for use Q 24 H for up to 3 days in cats.14

As time and treatment progress, patients undergoing defi nitive radiation therapy require additional oral pain medications, such as tramadol, buprenorphine, gabapentin, and amantadine.



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OTM buprenorphine (80–120 mcg/kg Q 12–24 H) or transdermal fentanyl liquid (2.7 mg/kg, one application) can be used to further alleviate pain when NSAIDs and other analgesics do not provide enough comfort.

De� nitive ChemotherapyAlthough it is not often recognized as a side effect of chemotherapy in veterinary patients, pain is possible due to: • Drug extravasation• Unique drug toxicities.

ExtravasationSevere tissue necrosis and pain occur when vesicant chemotherapy drugs, including doxorubicin, vincristine, and vinblastine, are administered extravascularly (Figure 5).15 Extravasation of doxorubicin results in severe tissue injury that may result in the need for surgical debridement, amputation, or euthanasia.15,16

Extravasation can be avoided by use of a perfectly placed, one-stick IV catheter and

vigilant observation.15,16 To reduce the risk of inadvertent catheter dislodgment and extravasation in dogs and cats that are too excited for catheter placement with physical restraint alone, chemical restraint—such as a neuroleptic analgesic technique combining a sedative/tranquilizer (eg, acepromazine, midazolam, dexmedetomidine) with an opioid—should be considered.

Once extravasation is known: • An attempt to aspirate the drug through the IV

catheter and then tissue cooling to induce local vasoconstriction and prevent further spread of the drug is recommended.16

• Evidence suggests that intravenous administration of the chelating agent dexrazoxane within 6 hours of doxorubicin extravasation may reduce severity of injury, but ideal dose and timing are unknown.16

• Anecdotally, topical 99% dimethyl sulfoxide applied 3 times per day and cold compresses applied up to 4 times per day for up to 2 weeks are recommended.15,16

• Use of the NSAID piroxicam has also been reported anecdotally,16 and other NSAIDs or opioids may be indicated depending on the severity and extent of tissue injury. NSAIDs and opioids may also be useful to reduce the occurrence of self-trauma following extravasation events that could lead to further local tissue injury. Although most recommendations for treatment

of extravasation injury are anecdotal, it is prudent to manage cases of suspected or confi rmed extravasation proactively, with combinations of topical dimethyl sulfoxide, cold compresses, NSAIDs, and opioids to reduce the risk for serious and potentially life-threatening tissue injury.

Sterile Hemorrhagic CystitisAcrolein is a metabolite of cyclophosphamide that is concentrated in the urinary bladder and induces sterile hemorrhagic cystitis (SHC), a painful and irritating condition that manifests as hematuria, pollakiuria, and stranguria without evidence of a bacterial infection.17,18 When SHC occurs, cyclophosphamide is often discontinued to reduce the risk for worsening clinical signs.

Treatment focuses on supportive care with oral pain medications, including opioids and NSAIDs, as no effective specifi c therapy for SHC exists. Prevention strategies include: • Co-administering furosemide at doses up to

2.2 mg/kg IV17

FIGURE 5. A 7-year-old, spayed female rottweiler—previously treated for diffuse large B-cell lymphoma at another practice—presented due to relapse, with a nonhealing ulcer over the right cephalic vein. The ulcer had reportedly developed 7 months prior to presentation, following the fi rst administration of vincristine. The referring veterinarian’s medical records indicated a change in the pet’s demeanor following the extravasation event, and the patient required a basket muzzle for subsequent treatments. The ulcer persisted until the dog’s death approximately 11 months after the extravasation event.



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• Splitting a cyclophosphamide bolus dose into an oral dose given over 3 to 4 days18

• Administering cyclophosphamide early in the day (to avoid overnight retention of the metabolite in the bladder)

• Providing large amounts of fresh water, and allowing frequent opportunities to empty the bladder.

Hand–Foot SyndromeChemotherapy pain due to hand–foot syndrome (HFS) or palmar–plantar dysesthesia is well documented in human patients following administration of chemotherapy drugs, including doxorubicin, capecitabine, and 5-fl uorouracil.19-22 HFS is characterized by diffuse erythema, swelling, and pain of the palmar and plantar surfaces of the hands, feet, or paws.19-23

While uncommon in veterinary medicine, HFS was reported as the dose-limiting toxicity in dogs treated with a liposomal formulation of doxorubicin.20-22 This toxicity was reduced, but not completely eliminated, by co-administration of pyridoxine, which allowed fewer treatment delays and dose reductions and a higher cumulative dose compared with placebo-treated controls.23

Hand–Foot Skin ReactionA similar reaction termed hand–foot skin reaction (HFSR) has been reported in humans following treatment with small molecule inhibitors, including sunitinib.19,24-25 HFSR is similar to HFS, but the lesions are histologically distinct and confi ned to pressure points. HFSR has not been reported in dogs treated with the small molecule inhibitors toceranib (an FDA-approved veterinary drug nearly identical in structure to sunitinib) or masitinib.26-29 As liposomal formulations of chemotherapy drugs and novel targeted chemotherapy agents become available in veterinary oncology, this side effect may be detected.

CHRONIC CANCER PAIN & PALLIATIVE TREATMENT Many veterinary patients with cancer are unable to receive defi nitive treatment; this may be due to metastatic disease at time of diagnosis, other life-limiting comorbidities, or lack of owner fi nances (Figure 1).

The central focus of palliative treatment is relief of pain and suffering. Although most patients undergoing palliative treatment for their cancer

will ultimately succumb to the disease, their quality of life can still be greatly improved for a period of time. Palliative treatment includes administration of pain medications and, potentially, various treatment modalities for the cancer itself.

Palliative SurgeryIn certain clinical situations, cancer that causes discomfort and/or pain may require surgical palliation. It is important for the practitioner to think about the whole patient and disease process when considering this treatment modality as a method of palliation.

The fi rst dictum of palliative medicine is the overriding goal of decreasing the patient’s pain. In the osteosarcoma case described on page 50, surgical amputation alone could be considered a palliative procedure; within 24 hours the patient felt better than it had prior to surgery. The distinction between palliation and defi nitive treatment in this case was the pursuit of chemotherapy, which created the potential for more side effects but improved long-term survival.

Gilson provides an excellent review of the indications and pitfalls of surgical cancer palliation.30 Continuous pain management using NSAIDs, opioids, gabapentin, and amantadine is necessary in the postoperative period and may be needed for continued palliation when additional therapies are not pursued.

Palliative RadiationWhat distinguishes palliative-intent from defi nitive-intent radiation therapy are goals of treatment, total dose of radiation delivered, and size of each fraction delivered. Palliative radiation therapy is designed to relieve clinical signs of pain and discomfort and avoid the potential for adverse side effects.

IndicationsIn patients in which defi nitive surgery and radiation therapy are not possible, palliative radiation therapy should be considered. Patients with gross soft tissue sarcomas, mast cell tumors, histiocytic sarcomas, and nasal tumors are all viable candidates for palliative radiation therapy.

Palliative radiation therapy is especially helpful for relieving pain that results from tumors that invade bone or other areas of the body. Pain sparing occurs as a result of the release of various anti-infl ammatory cytokines at the treatment site,



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Nasal Tumors: Advanced Techniques Lead to Fewer Side Effects Recent advances in cancer treatment delivery have diminished clinically signifi cant acute treatment side effects—effects commonly associated with signifi cant morbidity in dogs and cats—for nasal tumors.31

Intensity-modulated radiation therapy (IMRT), an advanced treatment delivery system, shapes the radiation beam to nearly any complex shape (Figure 6). The highly conformed shape of the beam allows for sharp “falloff” at the borders of the dose, resulting in diminished occurrence or elimination of side effects, which is possible because the energy from the radiation treatment beam is focused on the tumor, avoiding organs with sensitive pain receptors, such as the skin and oral mucosa.

This advanced therapeutic modality is particularly important in treatment of nasal tumors, which are adjacent to critical structures, such as the eyes and brain, and limits common side effects, such as mucositis, moist desquamation, and keratoconjunctivitis sicca (Figure 7).

Nasal Tumors: Advanced Techniques Lead to Fewer Side Effects

FIGURE 7. Patient with nasal tumor one week after defi nitive radiation therapy (19 fractions) using 3-dimensional conformal radiation therapy plan; note the extensive area of radiating moist desquamation present on the medial canthus and lips and areas of redness and dry desquamation present on the dorsum of the nose and caudal to the eye over the frontal sinuses (A). Patient with nasal tumor one week after defi nitive radiation therapy using advanced, highly conformal, IMRT plan (19 fractions). Although signifi cant moist desquamation is present, it is limited to a smaller area, radiating rostrally from the medial canthus (B). The patient in B only required NSAID pain medication during treatment, whereas the patient in A required multiple medications to manage painful side effects.

FIGURE 6. Axial-slice computed tomography scans of the nasal cavity in 2 dogs receiving defi nitive radiation therapy for a nasal tumor. Red and yellow areas are receiving 100% of the prescribed dose; blue and green areas are receiving 50% of the prescribed dose. Three-dimensional conformal radiation therapy plan (A); IMRT plan (B). Note that the volume of normal tissue, such as the mandible and skin, receive a signifi cantly reduced dose. * = tumor; + = tongue; # = lips

A B

A B



57

reduced osteolysis, and decreased tumor size.32 See Consider This Case: Palliative Radiation for Squamous Cell Carcinoma (page 58) for a case presentation that demonstrates the use of palliative radiation.

Tumors with a favorable long-term prognosis and postoperative microscopic local disease, such as an incompletely resected low- to intermediate-grade soft tissue sarcoma of the distal limb, should never be treated with palliative protocols. Owners who cannot afford defi nitive therapy should be counseled regarding the probability of recurrence (relatively low) and advised to consider palliative radiation therapy or amputation at a later date should the tumor recur.

The probability of a late side effect in slowly proliferating normal tissues, such as the central nervous system, smooth muscle, or bone, increases exponentially when palliative treatment protocols with large fraction sizes, such as those used in palliative radiation therapy, are employed.6

Differences in Therapy & Side EffectsWhile defi nitive treatments are delivered on a daily basis in 16 to 24 treatment sessions, palliative radiation therapy is delivered in 1 to 5 treatment sessions, either daily or once weekly. The fraction is also typically larger in palliative protocols, although the total dose delivered is smaller; defi nitive treatment fractions range from 2 to 3 Gy (total prescribed dose, 48–60 Gy), while palliative treatment fractions range from 4 to 8 Gy (total prescribed dose, 20–32 Gy).

Higher total doses delivered over a longer period of time are more likely to result in acute side effects in the treated areas, such as mucositis, dry desquamation, and moist desquamation. Lower total doses delivered over a short period of time are less likely to result in acute side effects, while still delivering a high enough dose to have an effect on the tumor, including pain relief, reduced tumor size, and decreased mechanical stretching due to space-occupying masses.

New techniques, such as IMRT, can be used to help minimize the potential for acute side effects in sensitive areas, such as the eye (see Nasal Tumors: Advanced Techniques Lead to Fewer Side Effects). Palliative ChemotherapyChemotherapy is frequently used with palliative intent in veterinary patients. Long-term successful outcomes are still possible when chemotherapy is

administered with palliative intent, but a reduction in tumor volume or improvement in overall survival time may not be the ultimate goal.

IndicationsPalliative-intent chemotherapy is intended to maximize quality of life by decreasing tumor burden or preventing tumor growth that would impair local function. Even in the face of incurable disease, chemotherapy can: • Decrease tumor burden, as is often the case with

nonresectable or metastatic high-grade mast cell tumors and histiocytic sarcoma

• Reduce the rate of tumor growth, ultimately preventing potentially life-threatening tumor sequelae, as is often the case with transitional cell carcinoma.

Therapeutic ApproachNoncytotoxic drugs, such as pamidronate and other bisphosphonates, may be useful in palliating bone pain or reducing risk for pathologic fractures associated with osteolysis. These drugs are frequently combined with chemotherapy, radiation therapy, or both in the treatment of canine appendicular osteosarcoma.33

IN SUMMARYCancer is a complex disease process that requires multimodal treatment, including surgery, radiation, chemotherapy, analgesics, and other nonpharmaceutical therapies. Pain can result not only from the cancer itself but also from the modalities that are employed to treat the cancer. Therefore, multimodal treatment should be used to manage cancer-related pain.

As the demand for, and availability of, veterinary cancer care services increase, veterinary practitioners are likely to encounter many of the clinical scenarios outlined in this article. Veterinarians are also likely to encounter pet owners who are interested in pursuing therapy for pets diagnosed with cancer, which requires an understanding of what treatment options are available, when palliative versus defi nitive care is indicated, and how to manage pain caused by cancer or its treatment.

CRI = constant rate infusion; CT = computed tomography; HFS = hand-foot syndrome; HFSR = hand-foot skin reaction; IMRT = intensity-modulated radiation therapy; NSAID =



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nonsteroidal anti-infl ammatory drug; OTM = oral transmucosal; SHC = sterile hemorrhagic cystitis

References1. Raslan AM, Burchiel KJ. Neurosurgical advances in cancer pain

management. Curr Pain Headache Rep 2010; 14:477-482.2. Bray JP, Worley DR, Henderson RA, et al. Hemipelvectomy:

Outcome in 84 dogs and 16 cats. A veterinary society of surgical oncology retrospective study. Vet Surg 2014; 43:27-37.

3. Simpson AM, Ludwig LL, Newman SJ, et al. Evaluation of surgical margins required for complete excision of cutaneous mast cell tumors in dogs. JAVMA 2004; 224:236-240.

4. Dernell WS, Withrow SJ, Kuntz CA, et al. Principles of treatment for soft tissue sarcoma. Clin Tech Small Anim Pract 1998; 13:59-64.

5. Kogel B, Terlinden R, Schneider J. Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs. Vet Anaesth Analg 2014; 41:297-304.

6. Abbo LA, Ko JC, Maxwell LK, et al. Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs. Vet Ther 2008; 9(2):83-93.

7. Ko JC, Freeman LJ, Barletta M, et al. Effi cacy of oral transmucosal and intravenous administration of buprenorphine before surgery for postoperative analgesia in dogs undergoing ovariohysterectomy. JAVMA 2011; 238(3):318-328.

8. Grasso S, Ko JC, Paranjape V, et al. Effects of transdermal fentanyl solution administration on isofl urane minimum alveolar concentration (MAC) reduction at 4- and 24-hour after its application in dogs. ACVAA & IVECC Proc, 2014.

9. Khan FM. The Physics of Radiation Therapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.

10. Taylor LP. Mechanism of brain tumor headache. Headache 2014; 54:772-775.

11. Hall EJ. Radiobiology for the Radiologist, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012.

12. Gillette EL, LaRue SM, Gillette SM. Normal tissue tolerance and management of radiation injury. Semin Vet Med Surg (Small Anim) 1995; 10:209-213.

13. Gillette EL, Mahler PA, Powers BE, et al. Late radiation injury to muscle and peripheral nerves. Int J Radiat Oncol Biol Phys 1995; 31:1309-1318.

14. King JN, Hotz R, Reagan EL, et al. Safety of oral robenacoxib in the cat. J Vet Pharmacol Ther 2012; 35(3):290-300.

15. Thamm DH, Vail DM. Aftershocks of cancer chemotherapy: Managing adverse effects. JAAHA 2007; 43:1-7.

16. Venable RO, Saba CF, Endicott MM, et al. Dexrazoxane treatment of doxorubicin extravasation injury in four dogs. JAVMA 2012; 240:304-307.

17. Charney SC, Bergman PJ, Hohenhaus AE, et al. Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990-1996). JAVMA 2003; 222:1388-1393.

18. Best MP, Fry DR. Incidence of sterile hemorrhagic cystitis in dogs receiving cyclophosphamide orally for three days without concurrent furosemide as part of a chemotherapeutic treatment for lymphoma: 57 cases (2007-2012). JAVMA 2013; 243:1025-1029.

19. Miller KK, Gorcey L, McLellan BN. Chemotherapy-induced hand-foot syndrome and nail changes: A review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol 2014; 71:787-794.

20. Anderson RT, Keating KN, Doll HA, et al. The hand-foot skin reaction and quality of life questionnaire: An assessment tool for oncology. Oncologist 2015; 20:831-838.

21. Vail DM, Kravis LD, Cooley AJ, et al. Preclinical trial of doxorubicin entrapped in sterically stabilized liposomes in dogs with spontaneously arising malignant tumors. Cancer Chemother Pharmacol 1997; 39:410-416.

22. Teske E, Rutteman GR, Kirpenstein J, et al. A randomized

An 11-year-old, castrated male mixed-breed dog presented for evaluation of changes in mentation, anorexia, and mucohemorrhagic nasal discharge that had been occurring for the previous 3 months. On physical examination, the patient was noted to be circling, and manipulation of the head and nose elicited aggression. The patient had a pain score of 5/5 on the in-clinic scale (See Table 3, Part 1: Pathophysiology & Assessment of Cancer Pain, May/June 2015, available at tvpjournal.com).

Diagnostic ApproachComputed tomography (CT) revealed a heterogeneous, contrast-enhancing mass in the nasal cavity, with destruction of the bones of the medial orbit. The mass invaded the cribriform plate and extended caudally for several centimeters into the forebrain, causing meningeal enhancement and lateral shifting of the falx cerebri (Figure 8). A biopsy of the mass was performed, and

squamous cell carcinoma was diagnosed on histopathology.

Therapeutic Approach1. Palliative radiation therapy (4

weekly treatments with an 8-Gy fraction size) was prescribed, using IMRT to spare the eyes and brain.

2. The patient also started receiving prednisone (0.5 mg/kg PO Q 24 H), OTM buprenorphine (120 mcg/kg Q 24 H), and gabapentin (10 mg/kg PO Q 12 H). When the patient returned 1

week later for the second dose of radiation therapy, the circling behavior had resolved and pain was no longer elicited when the face and head were touched. OTM buprenorphine was discontinued, and the patient was continued on gabapentin and prednisone for the duration of treatment.

OutcomeThe patient was euthanized 3 months after fi nishing treatment due to acute progression of neurologic signs and seizures.

Consider This Case: Palliative Radiation for Squamous Cell Carcinoma

FIGURE 8. CT scans of a patient with nasal squamous cell carcinoma; note the extensive bony destruction and forebrain invasion. Axial postcontrast CT scan at the level of the cribriform plate and orbit; note the extensive lysis of the medial orbit (*) and lysis of the nasal turbinates (+) (A). Sagittal reconstruction; note the focal contrast enhancement in the forebrain (arrows), destruction of the cribriform plate (^), and invasion into the frontal sinus (#) (B).

Consider This Case: Palliative Radiation for

A B



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controlled study into the effi cacy and toxicity of pegylated liposome encapsulated doxorubicin as an adjuvant therapy in dogs with splenic haemangiosarcoma. Vet Comp Oncol 2011; 9:283-289.

23. Vail DM, Chun R, Thamm DH, et al. Effi cacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: A randomized, double-blind clinical trial using a canine model. Clin Cancer Res 1998; 4:1567-1571.

24. Anderson R, Jatoi A, Robert C, et al. Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist 2009; 14:291-302.

25. Lacouture ME, Reilly LM, Gerami P, et al. Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 2008; 19:1955-1961.

26. London CA, Hannah AL, Zadovoskaya R, et al. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res 2003; 9:2755-2768.

27. Bernabe LF, Portela R, Nguyen S, et al. Evaluation of the adverse event profi le and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose. BMC Vet Res 2013; 9:190.

28. Hahn KA, Ogilvie G, Oglivie G, et al. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Intern Med 2008; 22:1301-1309.

29. Smrkovski OA, Essick L, Rohrbach BW, et al. Masitinib mesylate for metastatic and non-resectable canine cutaneous mast cell tumours. Vet Comp Oncol 2013.

30. Gilson SD. Principles of surgery for cancer palliation and treatment of metastases. Clin Tech Small Anim Pract 1998; 13:65-69.

31. Lawrence JA, Forrest LJ, Turek MM, et al. Proof of principle ocular sparing in dogs with sinonasal tumors treated with intensity modulated radiation therapy. Vet Radiol Ultrasound 2010; 51(5):561-570.

32. Goblirsch M, Mathews W, Lynch C, et al. Radiation treatment decreases bone cancer pain, osteolysis and tumor size. Radiat Res 2004; 161:228-234.

33. Fan TM, Charney SC, de Lorimier LP, et al. Double-blind placebo-controlled trial of adjuvant pamidronate with palliative radiotherapy and intravenous doxorubicin for canine appendicular osteosarcoma bone pain. J Vet Intern Med 2009; 23:152-160.

NICHOLAS RANCILIONicholas Rancilio, DVM, Diplomate ACVR (Radia-tion Oncology), is a clinical assistant professor at Purdue University College of Veterinary Medicine. He received his DVM from Michigan State Univer-sity, completed a small animal rotating internship at Washington State University, and completed a res-idency in veterinary radiation oncology at Purdue University. His interests include oncology patient palliative and hospice care, as well as image guided radiation therapy and stereotactic body radiotherapy.

CHRISTOPHER M. FULKERSON Christopher M. Fulkerson, DVM, MS, Diplomate ACVIM (Oncology), is a clinical assistant professor of veterinary medical oncology at Purdue Univer-sity College of Veterinary Medicine. He received his DVM and MS degrees from Purdue University, com-pleted a small animal rotating internship at Texas A&M University, and completed a residency in vet-erinary medical oncology at Purdue University.

2009; 23:152-160.

JEFF KO Jeff Ko, DVM, MS, Diplomate ACVAA, is a profes-sor of anesthesiology at Purdue University College of Veterinary Medicine, and is an anesthesiologist at Purdue Veterinary Teaching Hospital. He has taught anesthesiology at Virginia Tech, University of Florida, and Oklahoma State University. Dr. Ko has authored over 100 refereed articles and has recently published the book, Small Animal Anes-thesia and Pain Management: A Color Handbook.

strategies for managing cancer pain in dogs & cats part 2 ...€¦ · tumors, such as brain...

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