Tumors of the Skeletal System

Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs.

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Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology.

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies.

Background
Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking.

Objective
To evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin-based chemotherapy protocols.

Animals
Four hundred and seventy dogs with appendicular OSA.

Methods
A retrospective cohort study was performed comprising consecutive dogs treated (1997–2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m2 IV q21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m2 IV q14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m2 IV and doxorubicin 30 mg/m2 IV q21d for 3 cycles. Adverse events (AE) and DI were evaluated. Kaplan–Meier survival curves and Cox proportional hazards regression were used to compare disease-free interval (DFI) and survival time (ST) among protocols.

Results
The overall median DFI and ST were 291 days and 284 days, respectively. A lower proportion of dogs prescribed CARBO6 experienced AEs compared to other protocols (48.4% versus 60.8–75.8%; P = .001). DI was not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death.

Conclusions and Clinical Importance
Although choice of protocol did not result in significant differences in DFI or ST, the CARBO6 protocol resulted in a lower proportion of dogs experiencing AEs, which could be advantageous in maintaining high quality of life during treatment. DI was not a prognostic indicator in this study.

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Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs after amputation for treatment of appendicular osteosarcoma

Mast Cell Tumors

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.

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Preliminary evidence for biologic activity of toceranib phosphate (Palladia®) in solid tumours

Chronic lymphocytic leukemia (CLL) is a low-grade B cell lymphoma with circulating cells, often revealed by hyperlymphocytosis. Its diagnosis and therapeutic indications (not systematic) have been defined in 2018. In fact, CLL can be separated in two entities differentiating themselves by their IGHV mutational status, but the search of other prognostic parameters like TP53 disruption is mandatory before treatment. Numerous genetic alterations and mutations exist in CLL. CLL cells are highly dependent from their b-cell receptor stimulation and from their microenvironment, which takes a central place in disease progression. Infections, dysimmune manifestations, cancers and Richter transformation are classic complications, and patients have poor vaccine response even without a treatment. Chemoimmunotherapy is being challenged by the new highly active drugs such as Bruton tyrosine-kinase inhibitors (ibrutinib, acalabrutinib) and by the association of venetoclax and anti-CD20. Future treatment strategies might integrate both new drugs and classical chemoimmunotherapy. 

Meredith Gauthier

Papers

Preliminary evidence for biologic activity of toceranib phosphate (Palladia®) in solid tumours

[Chronic lymphocytic leukemia].