Journal Club: "Retrospective study of survival time and prognostic factors for dogs with small intestinal adenocarcinoma treated by tumour excision with or without adjuvant chemotherapy" by Smith et al.

Quick Clinical Takeaways

• Majority of dogs with small intestinal adenocarcinomas are male and older than 8 years old
• Most present with non-specific gastrointestinal signs. Pulmonary metastasis is uncommon, and the most common abdominal ultrasonographic abnormality includes an intestinal mass with partial or complete obstruction, sometimes mimicking a foreign body
• Age appeared to be statistically identified in this study to be a negative prognostic factor
• Overall median survival time was 544 days, with no significant differences in MSTs between dogs that underwent surgery alone vs those that underwent surgery and adjuvant chemotherapy
• Lymph node metastasis, extension to the serosa, lymphatic invasion and completeness of surgical margins appeared to have no association with survival times in this study

The oncology resident that I was working with yesterday saw a dog that had intestinal carcinomatosis. The patient was unwell and ultimately, palliation was opted as the patient was evaluated to be a poor candidate for surgery. That got me wondering however, about the negative prognostic indicators for this particular disease. I found this paper after digging around and really liked how well-structured their introduction was. So here we go!

Aims of the study

There is currently limited information on the prognosis of small intestinal adenocarcinoma (SICA) as well as the usefulness of chemotherapy for SICA patients. This study aims to evaluate and compare the survival times of SICA dogs treated with surgical excision and chemotherapy vs surgical excision alone. This study also aims to identify factors besides chemotherapy that may influence survival time.

Study Design

This study adopts a retrospective cross-sectional design. Data from two referral centres were collected from June 1 2006 to July 31 2016. 29 dogs met inclusion criteria.

Inclusion criteria:

• Received a diagnosis of adenocarcinoma within the small intestine
• Underwent surgery to excise the primary mass
• Sufficient information to determine if they have received any chemotherapeutic agents
  • Dogs were allocated into the chemotherapy group if they have received at least one dose
• Sufficient information to deduce if they were alive or not at the point of data collection
• Dogs with ongoing disease were included as well, including those with lymph node metastasis and local invasion into the adjacent mesentery

Results:

Signalment

• Median age of diagnosis: 9 years
• Majority (76%) of dogs were older than 8 years old
• Most dogs were male (21 vs 8 female)
• Common breeds affected: Mixed breed dogs (10), Labrador Retrievers (3), German Shepherd Dogs (2), Staffordshire Bull Terriers (2) and Border Collies (2)
• Median duration of clinical signs prior to diagnosis on histopathology was 86 days

Clinical signs:

Mainly non-specific gastrointestinal signs

• Vomiting (82%)
• Weight loss (64%)
• Anorexia (57%)
• Lethargy (50%)
• Diarrhoea (43%)
• Abdominal pain (18%)
• Constipation (7%)
• Palpable abdominal mass (26%)

Clinical pathology findings:

• Anaemia (29%)
• Hypoproteinaemia (26%)

Thoracic Imaging

• None had pulmonary metastasis on presentation

Abdominal ultrasound findings

• Intestinal mass (48%) with 38% experiencing partial or complete obstruction
• Regional lymphadenopathy (19%)
• Hepatomegaly (19%)
• Suspected foreign body (14%)
• Scant peritoneal effusion (10%)

Tumour locations on exploratory laparotomy

• 66% jejunum, 10% duodenum, 10% ileum, 3% duodenojejunal flexure, 3% jejunal-ileal junction, 3% ileum and caecum, 3% multiple segments

Histologic findings

• Serosal extension (22 out of 26 that described it; 85% )
• Lymphatic invasion (13 out of 27 that described it; 48%)
• 13 dogs had regional lymph node biopsy, of which metastasis was noted in 5 of them
• Other histologically confirmed metastasis sites included mesentery (38% of 29 dogs with available histopathology interpretation) and omentum (21%)

Adjuvant Chemotherapy

21 of the 29 included dogs underwent chemotherapy. 38% received sequential accelerated doxorubicin, 38% doxorubicin, 10% carboplatin, 5% toceranib phosphate, 5% vinorelbine and 5-fluorouracil.

Rescue protocols were used for 5 dogs with progressive disease and 3 of these dogs had more than 1 rescue protocol used.

Outcome

Overall median survival time was 544 days, with 1 and 2 year survival rates being 60% and 36% respectively based on Kaplan-Meier estimates.

Age as a continuous variable, age category (<8 years and >= 8 years), vomiting and anaemia were the variables identified on univariate analysis that may be associated with survival time. However, only age was independently associated with survival based on multivariate analysis. Dogs <8 years had an MST of 1193 days while dogs that were 8 years old or older had an MST of 488 days.

MSTs for dogs treated with surgery alone vs surgery and chemotherapy were not significantly different (488 days vs 611 days)

Evaluation of the study:

This paper was well structured. The introduction provided a quick summary about the disease and the paper was easy to follow. It also highlighted how like previously discussed, older male dogs appear to be predisposed to SICA [2]. Furthermore, it also identified that age may be a negative prognostic factor. Additionally, this study highlights how surgical excision could result in good patient outcomes as evidenced by the relatively long MSTs with or without chemotherapy.

The main limitations of this study however, would be the small sample size and the lack of standardisation of chemotherapy protocols for this disease. Firstly, only one chemotherapy dose administration was required to be included in the chemotherapy group. Hence, patients that discontinued their protocol midway may negatively influence the MST. Secondly, a variety of chemotherapy protocols were used in this study between patients; this could potentially mask any potential therapeutic benefit that a protocol may bring. This was further compounded by the small sample size which may result in any statistically significant benefits of a protocol being missed by pure chance. Thirdly, the median survival time was likely influenced by the inclusion of dogs that received rescue protocols and potential bias between clinicians on determining the timing of euthanasia. This study had the limitations of a retrospective study as well (will be discussed in a later post).

As highlighted by the authors in this study, a prospective, randomised clinical trial investigating this research question should be adopted with a large sample size in an ideal world. However, this often requires ethics approval which can be labourious and time consuming. Furthermore, SICA is a rare disease as well, only accounting for 0.3% of canine tumours [2]. Hence, this could make recruitment hard and the study may take up a long period of time. Nevertheless, I still believe that this study was designed beautifully while taking into account these limitations.

How this study can be adopted in clinical practice

• I would probably include this in my differential diagnosis list if a dog presents to me with chronic, non-specific gastrointestinal signs, particularly if they are male and older.
• The absence of a palpable abdominal mass on physical exam does not rule this out.
• Note that SICA may mimic a foreign body on radiographs and ultrasound, particularly if they cause partial or full obstruction
• This study highlights the utility of an abdominal ultrasound in ruling in or out SICA in addition to other diseases that result in gastrointestinal signs.
• If clients are cost-constrained and referral is not an option, SICA dogs probably can be managed at the primary care vet with a resection and anastomosis, supportive medications and q 3 monthly chest radiographs and abdominal ultrasound stagings +/- NSAIDs (COX-2 is overexpressed in 50% of canine intestinal adenocarcinomas [3], although I'm not sure how this can be used in a dog with GI signs like diarrhoea and vomiting)

Note: The information provided is for educational and informational purposes only and does not constitute professional medical advice, diagnosis, or treatment. Please seek a veterinarian if your pet is unwell.

References:

1. Smith, Ashley A., et al. ‘Retrospective Study of Survival Time and Prognostic Factors for Dogs with Small Intestinal Adenocarcinoma Treated by Tumor Excision with or without Adjuvant Chemotherapy’. Journal of the American Veterinary Medical Association, vol. 254, no. 2, Jan. 2019, pp. 243–50. DOI.org (Crossref), https://doi.org/10.2460/javma.254.2.243.
2. Patnaik, A. K., et al. ‘Canine Gastrointestinal Neoplasms’. Veterinary Pathology, vol. 14, no. 6, Nov. 1977, pp. 547–55. DOI.org (Crossref), https://doi.org/10.1177/030098587701400602.
3. Mcentee, M. F., et al. ‘Cyclooxygenase-2 Expression in Spontaneous Intestinal Neoplasia of Domestic Dogs’. Veterinary Pathology, vol. 39, no. 4, July 2002, pp. 428–36. DOI.org (Crossref), https://doi.org/10.1354/vp.39-4-428.