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High activity of sequential low dose chemo-modulating Temozolomide in combination with Fotemustine in metastatic melanoma. A feasibility study.

Guida M, Cramarossa A, Fistola E, Porcelli M, Giudice G, Lubello K, Colucci G - J Transl Med (2010)

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology; National Institute of Cancer, Bari, Italy. micguida@libero.it

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Presently, Dacarbazine (DTIC) remains the standard chemotherapy for MM with an overall response rate of approximately 10-15% with complete response in less than 5% of patients and a survival about 8-10 months... Patients with MM achieved overall response rates of nearly 20% with single-agent TMZ as similar as DTIC... Among nitrosurea analogs, fotemustine (FM) has been more extensively studied in MM, especially in Europe... It is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in MM with a response rate averaging 20%... A partial response (PR) was defined as a ≥ 30% decrease in the sum of longest diameter of all measured lesions... Stable disease (SD) was defined as no significant change in measurable and nonmeasurable disease... The toxicity profile was evaluated on 73 cycles of therapy delivered, 31 cycles for Cohort A (schedule 1-28) and 42 for Cohort B (schedule d1-21)... The main side effects are reported in table 2... The other PR occurred in a female with a disseminated disease including axillaries lymph nodes involvement, diffuse subcutaneous localizations, multiple liver metastases, and elevated LDH levels... After 2 cycles of therapy patient showed a dramatic response in all metastatic sites (Figure 2) and a significant decrease of LDH... In fact, our preliminary data showed that as compared to TMZ or FM single agent, the sequential regimen of the two drugs together significantly enhances their antitumoral activity inducing high response rate and regression also in visceral sites as bowel and liver... Surprisingly, an impressive lymphocytic (CD3+, CD4+, CD8+) and macrophage cells (CD68+) infiltration was also present (Figure 3, 4) meaning that immunomediated mechanisms have been also burst after TMZ-FM treatment, probably due to the massive disruption of neoplastic cell and consequent deliverance of tumoral associated antigens... In particular, the d1,8-28 schedule was characterized by a heavier G3-4 thrombocytopenia (3 of 7 patients) with respect to the d1-21 regimen (1 case of G3 thrombocytopenia) with a dose reduction in 4 patients in cohort A and in only 2 patients in cohort B, and chemotherapy delayed in 4 patients in cohort A and in 2 patients in cohort B... In summary, the d1-21 schedule resulted similar to the 1,8-28d schedule in term of activity, but it was superior in terms of tolerability and manageability guarantying the dose and timing planned... In the current study we demonstrated that the sequential combination of low dose TMZ and FM has a high activity in MM patients with an acceptable toxicity.

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Dramatic partial response in patient with liver, lymph nodes and subcutaneous metastases treated in Cohort B (schedule d1-21).
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Figure 2: Dramatic partial response in patient with liver, lymph nodes and subcutaneous metastases treated in Cohort B (schedule d1-21).

Mentions: In the Cohort B we reported 2 PR and 3 SD. The PR regarded one patient with subcutaneous, adrenal gland and bone lesions. The duration of response was 6 months and the overall survival was 10 months. The other PR occurred in a female with a disseminated disease including axillaries lymph nodes involvement, diffuse subcutaneous localizations, multiple liver metastases, and elevated LDH levels. After 2 cycles of therapy patient showed a dramatic response in all metastatic sites (Figure 2) and a significant decrease of LDH. The biopsy of a subcutaneous lesion performed after the third cycle of therapy confirmed the diagnosis of metastatic melanoma and revealed a diffuse regression of the neoplastic cells with the presence of abundant melanocitic pigment. Immunohistochemistry revealed an intense staining of neoplastic component for S100 protein, HMB 45 and MART 1. Moreover, an impressive lymphocytic (CD3+, CD4+, CD8+) and macrophage cells (CD68+) infiltration was present (Figure 3, 4). At present, after 13 months from starting therapy, this patient is alive in PR. Regarding the 3 patients with SD, 1 died after 10 months and the others are alive after 13 months and 14 months. The median overall survival of the entire group is more than 13 months. At a median follow up of 13 months, 7 of 14 patients are alive.


High activity of sequential low dose chemo-modulating Temozolomide in combination with Fotemustine in metastatic melanoma. A feasibility study.

Guida M, Cramarossa A, Fistola E, Porcelli M, Giudice G, Lubello K, Colucci G - J Transl Med (2010)

Dramatic partial response in patient with liver, lymph nodes and subcutaneous metastases treated in Cohort B (schedule d1-21).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992498&req=5

Figure 2: Dramatic partial response in patient with liver, lymph nodes and subcutaneous metastases treated in Cohort B (schedule d1-21).
Mentions: In the Cohort B we reported 2 PR and 3 SD. The PR regarded one patient with subcutaneous, adrenal gland and bone lesions. The duration of response was 6 months and the overall survival was 10 months. The other PR occurred in a female with a disseminated disease including axillaries lymph nodes involvement, diffuse subcutaneous localizations, multiple liver metastases, and elevated LDH levels. After 2 cycles of therapy patient showed a dramatic response in all metastatic sites (Figure 2) and a significant decrease of LDH. The biopsy of a subcutaneous lesion performed after the third cycle of therapy confirmed the diagnosis of metastatic melanoma and revealed a diffuse regression of the neoplastic cells with the presence of abundant melanocitic pigment. Immunohistochemistry revealed an intense staining of neoplastic component for S100 protein, HMB 45 and MART 1. Moreover, an impressive lymphocytic (CD3+, CD4+, CD8+) and macrophage cells (CD68+) infiltration was present (Figure 3, 4). At present, after 13 months from starting therapy, this patient is alive in PR. Regarding the 3 patients with SD, 1 died after 10 months and the others are alive after 13 months and 14 months. The median overall survival of the entire group is more than 13 months. At a median follow up of 13 months, 7 of 14 patients are alive.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology; National Institute of Cancer, Bari, Italy. micguida@libero.it

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Presently, Dacarbazine (DTIC) remains the standard chemotherapy for MM with an overall response rate of approximately 10-15% with complete response in less than 5% of patients and a survival about 8-10 months... Patients with MM achieved overall response rates of nearly 20% with single-agent TMZ as similar as DTIC... Among nitrosurea analogs, fotemustine (FM) has been more extensively studied in MM, especially in Europe... It is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in MM with a response rate averaging 20%... A partial response (PR) was defined as a ≥ 30% decrease in the sum of longest diameter of all measured lesions... Stable disease (SD) was defined as no significant change in measurable and nonmeasurable disease... The toxicity profile was evaluated on 73 cycles of therapy delivered, 31 cycles for Cohort A (schedule 1-28) and 42 for Cohort B (schedule d1-21)... The main side effects are reported in table 2... The other PR occurred in a female with a disseminated disease including axillaries lymph nodes involvement, diffuse subcutaneous localizations, multiple liver metastases, and elevated LDH levels... After 2 cycles of therapy patient showed a dramatic response in all metastatic sites (Figure 2) and a significant decrease of LDH... In fact, our preliminary data showed that as compared to TMZ or FM single agent, the sequential regimen of the two drugs together significantly enhances their antitumoral activity inducing high response rate and regression also in visceral sites as bowel and liver... Surprisingly, an impressive lymphocytic (CD3+, CD4+, CD8+) and macrophage cells (CD68+) infiltration was also present (Figure 3, 4) meaning that immunomediated mechanisms have been also burst after TMZ-FM treatment, probably due to the massive disruption of neoplastic cell and consequent deliverance of tumoral associated antigens... In particular, the d1,8-28 schedule was characterized by a heavier G3-4 thrombocytopenia (3 of 7 patients) with respect to the d1-21 regimen (1 case of G3 thrombocytopenia) with a dose reduction in 4 patients in cohort A and in only 2 patients in cohort B, and chemotherapy delayed in 4 patients in cohort A and in 2 patients in cohort B... In summary, the d1-21 schedule resulted similar to the 1,8-28d schedule in term of activity, but it was superior in terms of tolerability and manageability guarantying the dose and timing planned... In the current study we demonstrated that the sequential combination of low dose TMZ and FM has a high activity in MM patients with an acceptable toxicity.

Show MeSH
Related in: MedlinePlus