Anal sac anal gland adenocarcinoma — how combination therapy impacts outcome

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Surgery, drugs and nutraceuticals for anal sac anal gland adenocarcinoma, from the perspective of the surgeon and oncologist.

Tumors of the anal sac are often thought of as a local disease. But like all malignant conditions, the local development of the primary tumor, the behavior and spread of the tumor (grade and stage, respectively) and the outcome of intervention are all related to the systemic conditions that exist at any point during the disease process. The comprehension of any disease process (not just cancer) at this level, provides the veterinarian with a unique opportunity to intervene on many levels — both providing more options for the pet parent and improving outcomes for the patient. This article will define and describe ASAGASAC, and discuss traditional treatment interventions and outcomes as well as adjunct interventions from the perspective of functional food.

Tumors of the anal sac are uncommon and represent a small percentage of all skin tumors in dogs (< 2%). The most common malignant tumor of the perianal region is the anal sac (gland) carcinoma, accounting for 15% to 20% of all perianal tumors. These tumors are locally invasive and metastasize early in the course of disease. The average age of dogs diagnosed with this disease is ten or 11 years, and there does not appear to be a breed or sex predilection. These tumors are often noted as an incidental finding on a routine rectal examination. If patients present with clinical signs, the most frequently reported are perianal swelling, straining to defecate, licking at the perianal region and bleeding. It is important to measure the size of the tumor because this is prognostic. In some cases, the only presenting signs are polyuria and polydipsia secondary to hypercalcemia, which is the most common paraneoplastic syndrome seen in dogs with AGASACA, occurring in almost 30% of cases.

Diagnostics and staging

Standard pre-operative workup includes a CBC and blood chemistry, including an ionized calcium level, as well as urinalysis. Imaging studies are indicated, including three-view thorax radiographs to assess for pulmonary metastasis, and abdominal ultrasound to evaluate the regional lymph nodes, which are the most commonly affected with metastatic spread. Ultrasound is superior to abdominal radiographs for assessing the abdominal lymph nodes, but if ultrasound is not available, enlarged lymph nodes can be identified on radiographs. Computed tomography of the thoracic and abdominal cavities is a superior imaging modality and offers many advantages over radiographs and ultrasound, including cost in some cases. Aspirates/biopsy of the tumor or regional lymph nodes are necessary for clinical staging and therapeutic assessment, when possible.

The size of the anal sac tumor does not dictate the presence of metastatic disease. Abdominal ultrasound should be recommended in all anal sac tumor cases to rule out metastatic disease to regional lymph nodes. Up to 50% of patients do have metastasis to the sublumbar nodes at the time of presentation, and 10% to 20% have lung metastasis.

If ionized hypercalcemia is identified on pre-operative blood work, this needs to be corrected before anesthesia and surgery. Diuresis with 0.9% saline, furosemide and possibly prednisone will help normalize ionized calcium concentration prior to surgery.

Surgery for ASAGACA

The first stage of treatment for anal gland adenocarcinoma is surgical resection, which in many cases can be curative.

The anal sac is located between the external and internal anal sphincters. Malignant tumors commonly invade these muscles. Other regional structures of interest include the pudendal artery, vein and the caudal rectal nerve. Anal sacculectomy is considered a clean-contaminated surgery; antibiotics are given at the time of induction and, depending on the antibiotic, every 90 to 120 minutes during anesthesia. If there is no significant contamination during surgery, antibiotics are not needed in the post-operative period.

Pre-operative enemas are not recommended as they will liquefy the feces and contaminate the surgery site. Manual emptying of feces is often required prior to surgical prep of the surrounding skin. In the case of anal sac tumors, a purse string is not recommended because access to the anal sac duct opening is often required to obtain surgical margins. In some cases, part of the rectal wall will need to be resected and reconstructed. The patient is placed in the standard perineal position. A rolled towel is placed under the caudal abdomen and the cranial quadriceps muscles are padded against the table to prevent trauma to the femoral nerves.

Anal sac tumors are approached with a closed technique. The open technique will lead to contamination of the surrounding tissues with tumor cells and will not provide a clean surgical margin, often leading to local recurrence and providing an ongoing source of metastasis and hypercalcemia.

Surgery is approached with an incision directly over the palpable mass, and careful dissection is used to maintain the integrity of the tumor capsule. Maintaining the capsule is paramount to achieving local tumor control because wide resection in this area is not feasible due to the proximity of surrounding structures, including the rectal nerve, anus, rectum and sciatic nerve. If the tumor has adhered to the dermis or epidermis, it is possible and necessary to obtain a larger skin margin. If using electrosurgery, radiosurgery or carbon dioxide laser for dissection and hemostasis, care must be taken not to damage the caudal rectal nerve, external and internal anal sphincter, and the rectal wall.

Monopolar electrosurgery utilizes a grounding plate routinely placed under the patient. The energy source travels from the tip of the instrument through the local tissues, then through the body to the grounding plate, to continue the circuit. Bipolar tip attachments are preferred to minimize thermal damage as the energy only passes between the tips of the instrument.

After excision is complete, new gloves and instruments are used for local lavage and closure of the surgical wound to minimize the potential of seeding local tissues with tumor cells. If possible, external skin sutures or staples are avoided as they tend to collect fecal material along the incision in the post-operative period.

In the case of gross lymphadenopathy on ultrasound exam or CT, extirpation of the nodes is strongly recommended, especially in the hypercalcemic patient. The medial iliac and hypogastric lymph nodes are located in the region of the distal vena cava and bifurcation of the aorta. With mild levels of lymphadenopathy, removal is straightforward; but as the degree of lymphadenopathy increases, surrounding structures including the distal aorta, ureters and iliac vessels can make removal more challenging. Successful lymph node resection in this location is largely dependent on adequate exposure to the caudal peritoneal cavity and a thorough knowledge of the surrounding structures. The standard celiotomy incision will need to be extended caudally to the pelvic brim to allow for appropriate exposure to the region. Intra-operatively, it may be decided that the affected lymph nodes may not be resectable, and they are therefore biopsied prior to closure of the abdomen.

Complications include infection, fecal incontinence and recurrence of local disease. All these are minimized by appropriately prepping and positioning the patient; handling the tissue gently; providing meticulous hemostasis but minimizing the use of electrosurgery or laser; avoiding the use of external sutures or staples; and obtaining tumor-free margins (if possible). Submit all removed tissues intact; if it is worth removing, it is worth submitting.

Adjunct therapy

Adjunctive intervention with radiation and/or chemotherapy may be recommended based on the pre-surgical staging and the post-operative histopathology report.

Radiation

In cases where surgery is not complete, radiation therapy to the primary tumor site and regional lymph nodes will improve local control. Radiation therapy protocols range from 16 to 20 fractions on a Monday-through-Friday schedule. Acute side effects of radiation therapy can be moderate to severe and may result in colitis and rectal mucositis. During this period, an e-collar must be worn to prevent the dog from licking the area. One study found that dogs treated with surgery, radiation therapy (15 treatments) and chemotherapy (mitoxantrone) resulted in an overall survival of >900 days. In non-resectable tumors, hypofractionated radiation therapy has anecdotally been useful in palliation with a relatively high rate of response. Side effects such as rectal stricture may occur with this type of protocol.

Chemotherapy

The benefits of chemotherapy for this cancer are not well characterized; however, chemotherapy is often incorporated into treatment protocols. The most commonly used chemotherapy agents include doxorubicin, carboplatin, mitoxantrone, melphalan and gemcitabine. NSAIDs are often utilized for putative anti-cancer effects.

In a recent study assessing 42 dogs with AGASACA treated with surgery +/- chemotherapy, survival time was significantly associated with the presence of sublumbar LN and sublumbar LN extirpation. Median survival time was significantly shorter in dogs with sublumbar than in those without, and in dogs that underwent lymph node extirpation than in those that did not. Disease-free interval was significantly associated with the presence of sublumbar LNs, LN extirpation, and administration of platinum-containing chemotherapeutic agents. Median disease-free interval was significantly shorter in dogs with sublumbar LN than in those without; in dogs that underwent LN extirpation versus those that didn’t; and in dogs that received platinum chemotherapy versus those without.

Interestingly, survival time and disease-free interval did not differ among groups when dogs were categorized on the basis of histopathologic margins (complete versus marginal versus incomplete excision). One question raised by this study is whether chemotherapy was utilized in the “worst cases”, associating it with an unfavorable outcome to create a study bias.

In some cases, all three modalities (surgery, chemotherapy, radiation therapy) are used in the treatment of dogs with ASAGAC.

Non-resectable/metastatic tumors

No standard of care currently exists for advanced, non-resectable or metastatic tumors. However, several retrospective studies provide some data to help guide clinicians.

Hypofractionated radiation therapy (palliative radiation therapy)

One study assessed 77 dogs with measurable ASASACA; 38% experienced a partial response to RT. For dogs presenting with clinical signs related to the tumor, improvement or resolution of signs was noted in 63%. For dogs presenting with hypercalcemia of malignancy, resolution was noted in 31% with RT alone, and in an additional 46% with radiation, prednisone and/or bisphosphonates. The median overall survival was 329 days (range: 252 to 448 days) and the median progression-free survival was 289 days (range: 224 to 469 days).

A second study using a protocol of 8 × 3.8 Gy (total dose 30.4 Gy, over 2.5 weeks) was assessed in 28 dogs (15 underwent surgery, 13 underwent RT). At the time of presentation, 21% had a life-threatening obstipation and 25% were hypercalcemic. The progression-free interval and median survival time for surgery cases were 159 days and 182 days, both significantly lower than for radiation therapy cases, which were 347 days and 447 days. Surgery as well as RT led to relief of clinical signs.

Integrative and nutritional therapy

Humans with cancer commonly use physician-recommended or self-prescribed unconventional but complementary therapies in the form of herbs and nutritional supplements. An interesting insight into the widespread use of nutraceuticals to treat cancer in humans was described in a recent study in which investigators found that only 7% of human cancer patients used unconventional medical therapies when they were asked routine questions by their oncologist; however, when a questionnaire was given to patients across studies, it was revealed that 40% to 80% of cancer patients were actually using nutraceuticals to supplement their chemotherapy or radiation therapy protocols.

The high prevalence of nutraceutical use among human cancer patients further suggests that nutraceutical use in pets with cancer is likely to be as frequent, if not moreso. There is actually some good science behind the use of certain ocean-sourced natural ingredients, especially purified but not chemically-altered EPA and DHA sourced from fish and the naturally-isolated carbohydrate component of the New Zealand green-lipped mussel.

Cachexia (weight loss) in cancer patients, despite adequate nutrient intake,is a devastating consequence of malignancy in both human and veterinary patients. Alterations in resting energy expenditure and derangements in carbohydrate, protein and lipid metabolism have been documented in dogs prior to overt signs of cachexia.

EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid)

These Omega-3 fatty acids are found in high levels in fish oils. EPA is a potent anti-inflammatory mediator in the body, while DHA has its greatest impact in the brain and spinal cord. ALA, which is found in some seeds and plants and is marketed as a safe plant source of Omega-3s, requires the enzyme delta-6 desaturase to convert it into EPA and DHA in the body. Unfortunately, humans, dogs and cats have limited ability (dogs and humans) to no ability (cats) to convert ALA to EPA and DHA.

In general, the Omega-6 fatty acids, found in vegetable oils, corn oil, grapeseed oil, cottonseed oil, margarine, sesame oil, saturated fats and fast food products are pro-inflammatory. They keep the cells, tissues and body in a state of continued inflammation.  The body needs inflammation to heal wounds and fight infection and cancer cells, but too much inflammation over time leads to many systemic health conditions and diseases in dogs and cats. The body constantly strives to be in balance between inflammation and anti-inflammation, between Omega-6 and Omega-3. However, the body can’t produce or store Omega-3 or Omega-6 polyunsaturated fatty acids; therefore, it can only use what it is fed.

Studies of polyunsaturated fatty acids (PUFAs), especially the Omega-3 eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, have demonstrated prevention of carcinogen-induced tumors, the growth of solid tumors, and the occurrence of cachexia and metastatic disease in experimental tumor models. The proposed mechanisms in which these fatty acids elicit their effects may be related to the inhibition of cell proliferation and induction of apoptosis. In contrast, PUFAs of the Omega-6 series appear to enhance tumor development and metastases and are considered to be inflammatory in the tissues of the body. There is also epidemiologic evidence of an inverse relation between dietary Omega-3 fatty acid intake and the incidence of some cancers.

Some tumor cells have difficulty using lipids as a fuel source, although host tissues continue to oxidize lipids for energy. This finding led to the hypothesis that foods moderately high in certain fats may benefit animals with cancer, as compared with foods relatively high in carbohydrates. Pets in North America receive most of their nutrient intake from commercial dry pet foods. In general, these foods are usually high in soluble carbohydrate and relatively low in fat. These characteristics may make some commercial kibble-based foods less optimal for the nutritional management of animals with cancer.

High levels of EPA and DHA, as found in the triglyceride form of fish oil, are probably the most important nutraceutical to consider for animals with cancer. Several human epidemiologic studies have suggested that consumption of the correct form, source and dose of EPA and DHA is a beneficial adjunct to treating many cancers. The recommendation for feeding high levels of EPA and DHA to pets with cancer is based on in vitro cell culture studies; studies in rodent models evaluating different types of cancer; clinical trials in human patients with solitary and metastatic forms of cancer; and clinical trials in dogs treated for lymphoma and carcinoma.

Several hundred studies using laboratory models have evaluated the effects of EPA and DHA on tumorigenesis, tumor growth, metastasis and chemotherapy. EPA and DHA administration reduces the cancerous transformation of irradiated fibroblasts and inhibits proliferation and metabolism in various cancer cell lines; inhibits growth of aberrant cells; increases radiation sensitivity of cancer cells; inhibits growth of primary and metastatic tumors; demonstrates an enhanced effect of chemotherapeutic agents on cancer cells; decreases angiogenesis; reduces radiation damage to normal tissues; increases survival time when used with chemotherapy; increases disease-free interval when used with chemotherapy; and increases quality of life when used with chemotherapy.

Several well-controlled clinical trials have evaluated the use of a fish oil-supplemented food in normal dogs and those undergoing chemotherapy for lymphoma, and in a study of dogs being treated for carcinoma.

EPA and DHA supplementation were found to decrease or eliminate the metabolic alterations seen in dogs with stage IIIa and IVa lymphoma treated concurrently with doxorubicin chemotherapy, providing a significantly longer disease-free interval, longer survival times, and improved quality of life. It is extremely important to note that specifically increasing the serum DHA content was associated with longer disease-free intervals and survival times in dogs with stage III lymphoma. This is key because only the triglyceride form of fish oil provides superior absorption, bioavailability and cell membrane saturation of DHA.

Another controlled and randomized clinical trial evaluated the effect of fish oil supplementation on the acute effects of radiation injury in dogs with nasal tumors. Dogs fed the supplemented food had higher serum concentrations of EPA and DHA compared with control dogs. Higher serum levels of EPA and DHA were associated with lower plasma lactic acid concentrations, lower tissue concentrations of inflammatory mediators, improved quality of life scores, and a lower degree of histologic damage to normal tissues from radiation therapy.

Matrix metalloproteinases (MMPs)

MMPs are a family of zinc-dependent enzymes that play a key role in degrading basement membrane components and extracellular matrix. MMPs are pro-inflammatory, tissue-destructive, and thought to be involved in chronic inflammation and some neoplastic conditions. MMP activity is detectable in canine and feline neoplastic tissue and in the serum of tumor-bearing animals. MMP activity is higher in tumor tissue than in unaffected stromal tissue, indicating that MMPs may be involved in the pathogenesis of angiogenesis, tumor growth and metastasis. MMPs have been found to be significantly higher in naturally-developing malignant mammary gland tumors in dogs and most carcinomas compared with activities in normal tissues, and activities of tissue inhibitors of MMPs were lower in tumor tissue.

MMPs also play a significant role in the early and late inflammatory destruction of irradiated tissues. A study of dogs with osteosarcoma found that patients with activated levels of plasma MMPs had a significantly shorter survival time than dogs without. New Zealand green-lipped mussels (GLM) that are harvested as adults from the ocean, and immediately processed by cold live extraction methods, maintain their glycoprolex (glycogen-protein complex) component, which contains the active ingredient necessary for significant inhibition of MMP activation.

Together, these studies suggest that feeding a diet supplemented with a natural triglyceride (chemically unaltered) form of EPA and DHA, and the appropriate form (isolated carbohydrate) of a GLM extract, increases survival time of dogs undergoing single-agent cancer chemotherapy; increases the survival time of a subset of dogs undergoing single-agent cancer chemotherapy by more than 30% compared with similar dogs consuming an unsupplemented food; reduces the severity of some acute phases of radiation therapy, thereby improving quality of life; suppresses the clinical signs of cancer for longer intervals; and counteracts persistent metabolic changes found in many canine cancer patients.

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