916 CANCER September I , 1995, Volume 76, No. 5

of tumor neovascularization are difficult, because it is impos- sible to distinguish host vessels from tumor vessels in the par- affin sections (although the first attempts with frozen sections have been performed.') Factor VIII, a marker chosen by Ya- mazaki et al., has some critical matters of concerns relating to its sensitivity and specificity as a marker of lung capillariesg and tumor vessels.'O~'' I wonder if Yamazaki et al. considered other markers used in studies of neovas~ularization,'*-'~ such as CD31 (a member of the adhesion molecule family) or CD34 (glycosylated transmembrane protein present on immature hematopoietic precursor cell^).^

References

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Yamazaki K, Abe S, Takekawa H, Sukoh N, Watanabe N, Ogura S, et al. Tumor angiogenesis in human lung adenocarcinoma. Cancer 1994; 74:2245-50. Feld R, Arriagada R, Ball DL, Mattson K, Sorensen JB. Prognostic factors in non-small lung cancer: a consensus report. Lung Cancer

Mountain CF. A new international staging system for lung can- cer. Chest 1986;89 (4 Suppl):225S-33S. Yamashiro K, Yasuda S, Nagase A, Hirata T, Nojima T, Naga- shima K. Prognostic significance of an interface pattern of cen- tral fibrosis and tumor cells in peripheral adenocarcinoma of the lung. Hum Pafhol 1995;26:67-73. Wilde J, Haenselt V, Luft D, Luft P, Welker L. The impact of histological type and tumour localization on the prognosis in 1000 resected lung cancer patients with special view to adeno- carcinoma. Pneumonologie 1990;44:1287-93. Sobue T, Suzuki T, Fujimoto I, Doi 0, Tateishi R, Sat0 T. Prog- nostic factors for surgically treated lung adenocarcinoma pa- tients with special reference to smoking habit. Jpn ) Cancer Res

Takise A, Kodama T, Shimasato Y, Watanabe S, Suemasu K. His- topathologic prognostic factors in adenocarcinomas of the periph- eral lung less than 2 cm in diameter. Cattcer 1988;61:2083-8. Wang JM, Kumar S, Pye D, van Agthoven AJ, Krupinski J, Hunter RD. A monoclonal antibody detects heterogeneity in vascular endothelium of tumours and normal tissues. ln t ] Can- cer 1993;54:363-70. Kuzu I, Bicknell R, Harris AL, Jones M, Gatter KC, Mason DY. Heterogeneity of vascular endothelial cells with relevance to di- agnosis of vascular tumours. ) Clin Pathol 1992;45:143-8. Schlingemann RO, Rietveld FJR, Kwaspen F, van de Kerkhof PCM, de Waal RMW, Ruiter DJ. Differential expression of mark- ers for endothelial cells pericytes and basal lamina in the micro- vasculature of tumors and granulation tissue. Am ] Pathof

Horak ER, Leek R, Klenk, LeJeune S, Smith K, Stuart N, et al. Angiogenesis, assessed by platelet endothelial cell adhesion molecule antibodies, as indicator of node metastases and sur- vival in breast cancer. Lancet 1992;340:1120-4. Toi M, Kashitani J, Tominaga T. Tumor angiogenesis is an inde- pendent prognostic indicator in primary breast carcinoma. Int ] Cancer 1993;55:371-4. Vartaman RK, Weidner N. Correlation of intratumoral endothe- lial cell proliferation with microvessel density (tumor angiogen- esis) and tumor cell proliferation in breast carcinoma. A m JPathol

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Jaroslaw Sikora, M.D. Institute of Tuberculosis and Lung Disease Warsaw, Poland

Peripheral Neurotoxicity of Taxol in Patients Previously Treated with Cisplatin

We read with interest the article "Peripheral neurotoxicity of taxol in patients previously treated with cisplatin" by Dr. Ca- valetti and associates.' In this regard, we would like to draw the authors' attention to a patient followed in our oncology clinic.

A 66-year-old patient with metastatic breast cancer failed therapy with cyclophosphamide, methotrexate, and fluoro- uracil and was started on cisplatin (75 mg/m2) and etoposide every 3 weeks. She had a good partial response to this ther- apy, which was complicated by grade 11 peripheral neuropa- thy (Common Toxicity Criteria), manifested by mild numb- ness and tingling in the fingers and toes. The neuropathy re- mained stable over seven courses of chemotherapy (total cisplatin dose, 1050 mg), which was discontinued when we noted worsening liver function abnormalities, and a rising car- cinoembryonic antigen level.

Taxol therapy (175 mg/m2) was then initiated as a 3-hour infusion on a 3-weekly basis. Two weeks after the first course of taxol, the patient reported worsening numbness and tin- gling in her fingers and toes. After the second course of taxol, she noted difficulty buttoning her shirt and some clumsiness when walking. Her handwriting also appeared to be getting worse. As a result, the third course of taxol was delayed for a week and was given with a 15% dose reduction. The neurop- athy, however, got much worse, with a wide-based floppy gait and a complete inability to write or to button her shirt. Al- though clinical response to taxol was uncertain, the grade 111 neuropathy made it impossible to continue with this therapy any further. No motor or autonomic neurotoxicity was evi- dent, and the sensory neuropathy observed was not painful.

We would therefore like to suggest that: (1) Neuropathy in this setting may worsen even after the first course of taxol. The finding that cisplatin was administered within the last month before initiating taxol, as opposed to more than 12 months in the patients described by Dr. Cavaletti and col- leagues, may be germane in this regard. (2) Dose reduction, delays in therapy, and even taxol withdrawal may result from this neuropathy.

Reference

1 . Cavaletti G, Bogliun G, Marzorati L, Zincone A, Marzola M, Co- lombo N, et al. Peripheral neurotoxicity of taxol in patients pre- viously treated with cisplatin. Cancer 1995;75:1141-50.

Ajay Anand, M.D. Mark Huberman, M.D. Division of Hematology and Oncology New England Deaconess Hospital Harvard Medical School Boston, Massachusetts

Author Reply

The interesting letter by Drs. Anand and Huberman adds fur- ther material for discussion on the still unsettled issue of cu-

Correspondence 91 7

mulative neurotoxicity of cisplatin and paclitaxel (Taxol). They report the case of a woman previously treated with cis- platin who developed severely disabling peripheral neurotox- icity requiring drug withdrawal early in the course of pacli- taxel treatment. The authors suggest that the severe toxicity experienced by their patient was due to early cumulative tox- icity of the two drugs, but this assumption, although reason- able in general terms, is likely to have been biased in this par- ticular case by the very short interval between the treatments.

The time course of the severe sensory impairment de- scribed, in fact, more closely resembles the typical features of cisplatin neuronopathy, generally known as "off-treatment deterioration", rather than those reported in cases of pacli- taxel neuropathy. In fact, dorsal root ganglion neuron damage due to cisplatin treatment generally induces the onset of sen- sory symptoms and signs during the treatment, but their se- verity tends to increase up to 3-6 months after drug with- drawal, as demonstrated in both human and experimental studies.'-4 Paclitaxel neuropathy, on the contrary, frequently develops early during the treatment and does not progress un- til high total doses of the drug are delivered. The data on com- bination therapy are so far rather conflicting and several trials are ongoing. The preliminary results of one of these trials per- formed in our center have so far failed to demonstrate a critical increase in peripheral neurotoxicity such as those hypothe- sized in this patient.

Deeper insight into the pathogenesis of sensory symp- toms in the patient of Drs. Anand and Huberman might be obtained from the description of the follow-up of her neurop-

athy after paclitaxel discontinuation. Therefore, although it is theoretically possible that paclitaxel in some way enhanced the symptoms and signs of sensory disturbance in this patient, from the clinical data reported in the letter it is unclear whether its use was really responsible for the worsening of symptoms likely to be due to cisplatin treatment alone.

References

1. Grunberg SM, Sonka S, Stevenson LL, Muggia FM. Progressive paresthesias after cessation of therapy with very high dose cis- platin. Caiicw Chenzother Pharnzacol 1989; 2552-4.

2. Siegal T, Haim N. Cisplatin-induced peripheral neuropathy. Cancer 1990;66:1117-23.

3. LoMonaco M, hlilone M, Batocchi AP, LoMonaco M, Milone M, Batocchi AP, et al. Cisplatin neuropathy: clinical course and neu- rophysiologic findings. ] N e u r d 1992;239:199-204, Cavaletti G, Tredici G, Marmiroli l', Fabbrica D, Braga M. Off- treatment course of cisplatin-induced dorsal root ganglia neuro- nopathy in rats. I n Vizw 1994;8:313-6.

4.

Guido Cavaletti Department of Neurology S. Gerard0 Institute for Biomedical Sciences University of Milan Monta, Italy Giovanni Tredici Institute of Human Anatomy University of Milan Milan, Italy