Cats received vinorelbine presented longer time to progression and overall survival time, although there were not statistical significant. Incidence of gastrointestinal toxicity was significant lower in cats treated with vinorelbine when compared to those receiving doxorubicin, and neutropenia was the most common documented adverse event in cats administered vinorelbine. In conclusion, cats with FMC treated with vinorelbine had similar efficacy but less GI toxicity compared to cats treated with doxorubicin; therefore, vinorelbine may be an appropriate alternative agent to be used in treating FMC. Neuter status, ulceration of tumor and biological response were prognostic factors in the study.
34
Figures
Figure 1. The Kaplan-Meier curve for time to progression (TTP) of the two groups.
The median TTP for VRL group (solid line, n =7) and DOX (dashed line, n =19) was 115 days and 102 days respectively. No significance was found in median TTP between two groups (P =0.949)
Figure 2. The Kaplan-Meier curve for overall survival time (OST) of the two groups.
The median OST was 352 days for VRL group (solid line, n =7) and 284 days for DOX group (dashed line, n =19). No significant difference was observed (P =0.948)
36
Figure 3. The Kaplan-Meier curve for time to progression (TTP) between gender.
The median TTP was 119 days for intact female cats (solid line, n =9) and 63 days for neutered cats (dashed line, n =17). (P =0.021)
Figure 4. The Kaplan-Meier curve for time to progression (TTP) among different biological responses.
The median TTP was 119 days for responders (solid line, n =15) and 28 days for non-responders (dashed line, n =11). (P =0.008)
38
Figure 5. The Kaplan-Meier curve of time to progression (TTP) for ulceration group.
The median TTP was 119 days for cats without ulcerative tumors (solid line, n =17) and 37 days for cats with ulcerative tumors (dashed line, n =9). (P =0.080)
Figure 6. The Kaplan-Meier curve of overall survival time (OST) for different tumor distribution groups.
The median OST was 446 days for cats with unilateral tumors (solid line, n =16) and 254 days for cats with bilateral tumors (dashed line, n =10). (P =0.069)
40
Figure 7. The Kaplan-Meier curve of overall survival time (OST) among different biological responses.
The median OST was 446 days for responders (solid line, n =15) and 232 days for non-responders (dashed line, n =11). (P =0.012)
Tables
Table 1. Comparison of characteristics for vinorelbine and doxorubicin.
Agent Vinorelbine Doxorubicin
Classification Semi-synthetic vinca alkaloid Anthracyclines
Mechanism
• Inhibition the function of RNA and DNA for dogs smaller than 15 kg Dosing
interval
Weekly for 4 times and then
biweekly for 4 times Usually every 2-3 weeks Route IV over 5-10 minutes IV infusion over 30 minutes
• Extravasation vesicant
• GI toxicity
• Hypersensitivity
• Cumulative dose-related cardiotoxicity and nephrotoxicity
IV, intravenous; TCC, transitional cell carcinoma; MCT, mast cell tumor; NSCLC, non-small-cell lung cancer; LSA, lymphoma; MGT, mammary gland tumor; STS, soft tissue sarcoma; GI, gastrointestinal
42
Table 2. Modified World Health Organization staging system for feline mammary carcinoma.
T: tumor size
T1 <2 cm maximum diameter
T2 2-3 cm maximum diameter
T3 >3 cm maximum diameter
N: regional lymph node
N0 No evidence of metastasis
N1 Evidence of metastasis
M: distant metastasis
M0 No evidence of distant metastasis
M1 Evidence of distant metastasis
Stage
1 T1, N0, M0
2 T2, N0, M0
3 T3, N0-1, M0; Any T, N1, M0
4 Any T, Any N, M1
Table 3. Veterinary cooperative oncology group - common terminology criteria for
Vomiting <3 episode in 24 h, medical
Diarrhea Increase of up to 2 stools per day LLN, lower limit of normal; IV, intravenous; SC, subcutaneous; TP, total parental nutrition; PPN, partial parental nutrition; ADL, activities of daily living (eating, sleeping, defecating and urinating)
44
Table 4. Comparison of characteristics between two groups.
VRL group DOX group P value
Age (years) 0.878
Median (range) 12 (6-14) 12 (7-15)
Body weight (kg) 0.388
Median (range) 4.06 (2.66-4.86) 3.78 (2.56-5.82)
Breed 1.000
Mixed 5 (71.4%) 12 (63.2%)
Persian 1 (14.3%) 4 (21.1%)
Others 1 (14.3%) 3 (15.8%)
Gender 0.186
Female intact 1 (14.3%) 8 (42.1%)
Female neutered 6 (85.7%) 11 (57.9%)
Table 5. Comparison of tumor demographics between two groups.
VRL group DOX group P value
Gross disease when received chemotherapy
a. Two cats in VRL group and 4 cats in DOX group were lack of histopathological diagnosis.
b. Three cats in VRL group and 10 cats in DOX group were lack of information about surgical margin and lymphatic and vascular invasion.
c. Two cats in VRL group and 12 cats in DOX group were lack of tumor grade.
46
Table 6. Comparison of clinical stage between two groups.
VRL group DOX group P value
a. One cat in DOX group were lack of information about tumor size.
b. One cat in VRL group and 8 cats in DOX group were lack of information about status of lymph node.
c. Two cats in DOX group had not sufficient information to be accurately staged.
Table 7. Total numbers and dosage of vinorelbine given in VRL group.
Dosage (mg/m2) of vinorelbine
Total Number of Doses Given
7.36 2
7.50 2
8.00 6
8.25 1
8.28 2
8.50 1
9.30 1
9.70 1
10.00 1
10.30 1
10.35 9
10.40 5
11.40 1
11.50 10
12.60 1
48
Table 8. Total numbers of doses and cumulative dosage of doxorubicin in DOX group.
Dosage (mg/m2) of doxorubicin
Total Number of Doses Given
Cumulative dosage (mg/m2) of doxorubicin
Total number of Cases
20.0 10 20.0 1
22.2 1 24.7 1
22.3 1 25.0 4
23.5 1 40.0 2
24.7 1 45.0 3
25.0 26 45.7 1
50.0 2
70.0 1
75.0 1
95.0 1
97.3 1
100.0 1
Table 9. Response to treatment in two groups.
Measurable disease VRL group DOX group P value
Objective response rate 0.058
Complete remission 1 (25.0%) 0 (0%)
Partial remission 2 (50.0%) 2 (18.2%)
Stable disease 1 (25.0%) 2 (18.2%)
Progressive disease 0 (0%) 7 (63.6%)
Non-measurable disease
Response 0.077
Non-CR/non-PD a 3 (100.0%) 4 (50.0%)
Progressive disease 0 (0%) 4 (50.0%)
All patients
Biological response rate 0.008
Biological response b 7 (100.0%) 8 (42.1%)
Progressive disease 0 (0%) 11 (57.9%)
a. The cases maintained with non-measurable disease at the beginning and the end of treatment.
b. Biological response rate was defined as the total number of cases had been
experienced complete remission, partial remission, stable disease and Non-CR/non-PD divided by the number of cases treated.
50
Table 10. Summary of median time to progression (TTP) and median overall survival time (OST) for two groups.
VRL group DOX group P value
Median TTP 115 days 102 days 0.949
Median OST 352 days 284 days 0.948
Table 11. Toxicities of treatment in two groups.
VRL group a episodes (%)
DOX group b
episodes (%) P value
Vomiting 8 (18.2%) 19 (47.5%) 0.004
Grade 1 8 (18.2%) 16 (40.0%)
Grade 2 0 (0%) 3 (7.5%)
Grade 3 0 (0%) 0 (0%)
Anorexia 5 (11.4%) 19 (47.5%) 0.000
Grade 1 3 (6.8%) 5 (12.5%)
Grade 2 2 (11.4%) 13 (32.5%) 0.001
Grade 3 0 (0%) 1 (2.5%)
Diarrhea 0.598
Grade 1 3 (6.8%) 4 (10%)
Neutropenia 19 (43.2%) 0 (0%) 0.000
Grade 1 6 (13.6%) 0 (0%)
Grade 2 5 (11.4%) 0 (0%)
Grade 3 6 (13.6%) 0 (0%)
Grade 4 2 (4.5%) 0 (0%)
a. Forty-four doses of vinorelbine were administered in VRL group.
b. Forty doses of doxorubicin were administered in DOX group.
52
Table 12. Univariate analysis of time to progression (TTP) for factors about patient’s demographics.
b. Nine cats were lack of information of status of lymph node.
c. Two cats cannot be staged.
d. Three cats did not undergo surgery.
Table 13. Univariate analysis of time to progression (TTP) for factors about tumor
Biological responder d 15 119
Non-biological responder 11 28
a. Ten cats were lack of information of subtype.
b. Fourteen cats were lack of information about tumor grade.
c. Thirteen cats were lack of information about lymphatic and vascular invasion.
d. Biological response rate was defined as the total number of cases had been experienced complete remission, partial remission, stable disease and Non-CR/non-PD divided by the number of cases treated.
54
Table 14. Multivariate analysis of possible prognostic factors for time to progression.
Factor n Hazards ratio 95% CI P value
Gross tumor 0.699 0.101-4.835 0.717
No 11
Yes 15
Neuter status 5.377 1.406-20.562 0.014
Intact female 9 Neutered female 17
Ulceration 1.189 0.466-3.035 0.717
No 17
Yes 9
M stage 8.730 0.868-87.811 0.066
M0 11
M1 15
Biological response 19.397 3.680-102.249 0.000
Responder a 15
Non-responder 11
a. Biological response rate was defined as the total number of cases had been experienced complete remission, partial remission, stable disease and Non-CR/non-PD divided by the number of cases treated.
Table 15. Univariate analysis of overall survival time (OST) for factors about patient’s
a. Three cats did not undergo surgery.
b. One cat was lack of information of tumor size.
c. Nine cats were lack of information of status of lymph node.
d. Two cats cannot be staged.
56
Table 16. Univariate analysis of overall survival time (OST) for factors about tumor features and response of treatment.
Biological responder d 15 446
Non-biological responder 11 232
a. Ten cats were lack of information of subtype.
b. Fourteen cats were lack of information about tumor grade.
c. Thirteen cats were lack of information about lymphatic and vascular invasion.
d. Biological response rate was defined as the total number of cases had been experienced complete remission, partial remission, stable disease and Non-CR/non-PD divided by the number of cases treated.
Table 17. Multivariate analysis of possible prognostic factors for overall survival time.
Factor n Hazards ratio 95% CI P value
Body weight (kg) 2.057 0.279-15.140 0.479
<3.87 13
>3.87 13
Age (years) 3.002 0.442-20.381 0.261
≥12 14
<12 12
Location 1.472 0.197-10.985 0.706
Unilateral 16
Bilateral 10
Received rescue
chemotherapy 1.013 0.193-5.333 0.987
No 20
Yes 6
Ulceration 5.192 1.137-23.706 0.034
No 17
Yes 9
Biological response 4.027 1.004-16.152 0.049
Responder a 15
Non-responder 11
a. Biological response rate was defined as the total number of cases had been experienced complete remission, partial remission, stable disease and Non-CR/non-PD divided by the number of cases treated.
58
REFERENCES
[1] Borrego JF, Cartagena JC, Engel J. Treatment of feline mammary tumours using chemotherapy, surgery and a COX-2 inhibitor drug (meloxicam): a retrospective study of 23 cases (2002-2007). Vet Comp Oncol 7:213–221, 2009.
[2] De Campos CB, Nunes FC, Lavalle GE, Cassali GD. Use of surgery and carboplatin in feline malignant mammary gland neoplasms with advanced clinical staging. In Vivo 28(5):863-866, 2014.
[3] Dorn CR, Taylor DO, Schneider R, Hibbard HH, Klauber MR. Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst 40:307–318, 1968.
[4] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247, 2009.
[5] Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, Garcia-Giralt E, Keiling R, Namer M, Closon MT. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 11(7):1245-1252, 1993.
[6] Giménez F, Hecht S, Craig LE, Legendre AM. Early detection, aggressive therapy:
optimizing the management of feline mammary masses. J Feline Med Surg 12(3):214-224, 2010.
[7] Gong SJ, Rha SY, Jeung HC, Roh JK, Yang WI, Chung HC. Bilateral breast cancer:
differential diagnosis using histological and biological parameters. Jpn J Clin Oncol
37(7):487-492, 2007.
[8] Grant IA, Rodriguez CO, Kent MS, Sfilgoi G, Gordon I, Davis G, Lord L, London CA. A phase II clinical trial of vinorelbine in dogs with cutaneous mast cell tumors.
J Vet Intern Med 22(2):388-393, 2008.
[9] Gustafson DL, Page RL. Cancer chemotherapy. In: Withrow SJ, Vail DM, Page RL, ed. Withrow & MacEwen's small animal clinical oncology. Saunders Elsevier, St.
Louis, 157-179, 2013.
[10] Hahn KA, Adams WH. Feline mammary neoplasia: biological behavior, diagnosis, and treatment alternatives. Feline Pract 25: 5–11, 1997.
[11] Hartman M, Czene K, Reilly M, Adolfsson J, Bergh J, Adami HO, Dickman PW, Hall P. Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J Clin Oncol 20;25(27):4210-4216, 2007.
[12] Hayden DW, Nielsen SW. Feline mammary tumours. J Small Anim Pract 12: 687–
698, 1971.
[13] Ito T, Kadosawa T, Mochizuki M, Matsunaga S, Nishimura R, Sasaki N. Prognosis of malignant mammary tumor in 53 cats. J Vet Med Sci 58: 723–726, 1996.
[14] Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 13(10):2567-2574, 1995.
[15] Kaye ME, Thamm DH, Weishaar K, Lawrence JA. Vinorelbine rescue therapy for dogs with primary urinary bladder carcinoma. Vet Comp Oncol 13(4):443-451, 2015.
[16] Kristal O, Lana SE, Ogilvie GK, Rand WM, Cotter SM, Moore AS. Single agent chemotherapy with doxorubicin for feline lymphoma: a retrospective study of 19
60
cases (1994-1997). J Vet Intern Med 15(2):125-130, 2001.
[17] Kristiansen VM, Peña L, Díez Córdova L, Illera JC, Skjerve E, Breen AM, Cofone MA, Langeland M, Teige J, Goldschmidt M, Sørenmo KU. Effect of Ovariohysterectomy at the Time of Tumor Removal in Dogs with Mammary Carcinomas: A Randomized Controlled Trial. J Vet Intern Med 30(1):230-241, 2016.
[18] Levêque D, Quoix E, Dumont P, Massard G, Hentz JG, Charloux A, Jehl F.
Pulmonary distribution of vinorelbine in patients with non-small-cell lung cancer.
Cancer Chemother Pharmacol 33(2):176-178, 1993.
[19] MacDonald V. Chemotherapy: Managing side effects and safe handling. Can Vet J 50(6): 665–668, 2009.
[20] MacEwen EG, Hayes AA, Harvey HJ, Patnaik AK, Mooney S, Passe S. Prognostic factors for feline mammary tumors. J Am Vet Med Assoc 185: 201–204, 1984.
[21] Maldonado G, Greenland S. Simulation study of confounder-selection strategies.
Am J Epidemiol 1;138(11):923-936, 1993.
[22] Martín De Las Mulas J, Millán Y, Bautista MJ, Pérez J, Carrasco L. Oestrogen and progesterone receptors in feline fibroadenomatous change: an immunohistochemical study. Res Vet Sci 68(1):15-21, 2000.
[23] Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; Spanish Breast Cancer Research Group (GEICAM) trial. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 8(3):219-225, 2007.
[24] Matos AJ, Baptista CS, Gärtner MF, Rutteman GR. Prognostic studies of canine
and feline mammary tumours: the need for standardized procedures. Vet J 193(1):24-31, 2012.
[25] Mauldin GN, Matus RE, Patnaik AK, Bond BR, Mooney SC. Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats. J Vet Intern Med 2: 60–65, 1988.
[26] McNeill CJ, Sorenmo KU, Shofer FS, Gibeon L, Durham AC, Barber LG, Baez JL, Overley B. Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma. J Vet Intern Med 23(1):123-129, 2009.
[27] Mills SW, Musil KM, Davies JL, Hendrick S, Duncan C, Jackson ML, Kidney B, Philibert H, Wobeser BK, Simko E. Prognostic value of histologic grading for feline mammary carcinoma: a retrospective survival analysis. Vet Pathol 52(2):238-249, 2015.
[28] Misdorp W. Tumors of the mammary gland. In: Meuten DJ, ed. Tumors in domestic animals. Ames, Iowa, 575-606, 2002.
[29] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2, 2016.
[30] Ngan VK, Bellman K, Panda D, Hill BT, Jordan MA, Wilson L. Novel actions of the antitumor drugs vinflunine and vinorelbine on microtubules. Cancer Res 15;60(18):5045-5051, 2000.
[31] Novosad CA, Bergman PJ, O'Brien MG, McKnight JA, Charney SC, Selting KA, Graham JC, Correa SS, Rosenberg MP, Gieger TL. Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma:
67 cases. J Am Anim Hosp Assoc 42(2):110-120, 2006.
[32] O'Keefe DA, Sisson DD, Gelberg HB, Schaeffer DJ, Krawiec DR. Systemic toxicity associated with doxorubicin administration in cats. J Vet Intern Med
62
7(5):309-317, 1993.
[33] Overley B, Shofer FS, Goldschmidt MH, Sherer D, Sorenmo KU. Association between ovarihysterectomy and feline mammary carcinoma. J Vet Intern Med 19:
560–563, 2005.
[34] Pierro JA, Mallett CL, Saba CF. Phase I Clinical Trial of Vinorelbine in Tumor-Bearing Cats. J Vet Intern Med 27(4):943-948, 2013.
[35] Poirier VJ, Burgess KE, Adams WM, Vail DM. Toxicity, dosage, and efficacy of vinorelbine (Navelbine) in dogs with spontaneous neoplasia. J Vet Intern Med 18(4):536-539, 2004.
[36] Reiman RA, Mauldin GE, Neal Mauldin G. A comparison of toxicity of two dosing schemes for doxorubicin in the cat. J Feline Med Surg 10(4):324-331, 2008.
[37] Seixas F, Palmeira C, Pires MA, Bento MJ, Lopes C. Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J 187(1):65-71, 2011.
[38] Sorenmo KU, Worley DR, Goldschmidt MH. Tumors of the Mammary Gland. In:
Withrow SJ, Vail DM, Page RL, ed. Withrow & MacEwen's small animal clinical oncology. Saunders Elsevier, St. Louis, 538-556, 2013.
[39] Veterinary cooperative oncology group - common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 9: 1–30, 2011.
[40] Zappulli V, De Zan G, Cardazzo B, Bargelloni L, Castagnaro M. Feline mammary tumours in comparative oncology. J Dairy Res 72:98-106, 2005.