Conventional Chemotherapy

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Treatment of the non-ALCL T-cell lymphomas with conventional chemotherapy designed for B-cell lymphomas has had only limited success. Common anthracycline-containing regimens result in low response rates and short durations of remission, and the vast majority of patients develop resistant disease. For example, Armitage et al. evaluated 134 cases of PTCL diagnosed at three centers from 1973 to 1986: 80 patients had been treated with intensive regimens such as CHOP [cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone] with or without bleomycin, CAP-BOP (cyclophos-phamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone), COMLA (cyclophosphamide, vincristine, methotrexate, and cytosine arabinoside), and MACOP-B (methotrexate, doxorubicin, cyclophos-phamide, vincristine, prednisone, and bleomycin).21 While the median survival was 17 months and the 4-year survival was 28% for all 134 patients, for the 80 patients who received intensive combination chemotherapy, 50% achieved a CR, with the 4-year durability of remission being 41% and the overall survival of this intensively treated group being 45%. However, the 4-year disease-free survival for those with stage IV disease, comprising 50% of the patients, was only 10%. Ansell et al.77 evaluated 78 patients seen at the Mayo Clinic with T-cell lymphomas from 1985 to 1995; most received doxorubicin-containing regimens, including CHOP, ProMACE-CytaBOM (methotrexate, prednisone, doxorubicin, cyclophosphamide, etopo-side, cytarabine, bleomycin, and vincristine), and m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone). The median overall survival duration for the 78 patients on study was 22 months (range 1-105 + months). The median survival for high-risk IPI patients was 6 months, compared to 15 months for high-intermediate IPI patients, and 24 months for low-intermediate IPI patients, and the median survival for the low-risk group was not reached; the differences in survival rates were statistically significant. There were no significant differences in response rates among the T-cell subtypes, and univariate analysis showed no statistically significant survival differences among various T-cell subgroups. RĂ¼diger et al. studied 96 cases of non-ALCL PTCL evaluated in the Non-Hodgkin's Lymphoma Classification Project, 70% of whom had received doxorubicin-containing regimens. The 5-year overall survival was 26%, and the failure-free survival was 20%.2 Physicians from French and Belgian centers evaluated 288 PTCL patients (60 cases of T-ALCL and 228 cases of non-ALCL PTCL) treated with anthracycline-contain-ing regimens, including m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vin-cristine, and dexamethasone), ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, and pred-nisone), and NCVB (mitoxantrone, cyclophosphamide, vindesine, bleomycin, and prednisone), followed by consolidation and maintenance therapies or autolo-gous transplantation in many cases. The CR rates were 54% for all patients, 72% for those with ALCL, and 49% for those with non-ALCL T-cell lymphomas, and 5-year survival rates were 41, 64, and 35%, respectively. Five factors adversely and significantly influenced survival by multivariate analysis: age greater than 60 years, advanced stage, elevated LDH, performance status, and non-ALCL T-cell lymphoma.22 Lopez-Guillermo et al.76 evaluated 174 T-cell lymphomas from Spanish institutions; 30 were ALCL and the rest consisted of PTCL unspecified, angioimmunoblastic T-cell, angiocentric, intestinal T-cell, and hepatosplenic gamma/delta T-cell lymphomas. Most patients received CHOP-like therapy. CR rates were 69% for ALCL cases and 45% for other PTCL subtypes, with a median survival of 65 months for ALCL and 20 months for other PTCL, and 4-year survival probabilities of 62 and 32%, respectively. From MD Anderson Cancer Center, Melnyk et al. evaluated 68 T-cell lymphoma patients treated from 1984 to 1995 with anthracycline-containing regimens such as CHOP-bleomycin alternating with DHAP (dexamethasone, cisplatin, and cytarabine), CHOP-bleomycin alternating with CMED (cyclophosphamide, etoposide, methotrexate, and dexamethasone), CHOP-bleomycin alternating with OPEN (vincristine, etoposide, mitox-antrone, and prednisone), or alternating triple therapy consisting of ASHAP (cytarabine, doxorubicin, cisplatin, and methylprednisolone), MBACOS (doxorubicin, cyclophosphamide, vincristine, bleomycin, methylpred-nisolone, and methotrexate), and MINE (mesna, ifos-famide, mitoxantrone, and etoposide).23 Similar to reports of others, the CR rate was 65%, the 5-year failure-free survival rate was 38%, and overall survival result was 38%, and those with ALCL had better results. Interestingly, a significant number of deaths in patients with non-ALCL T-cell lymphomas occurred 3 years after treatment, many of whom died due to late relapses.

Other investigators also have reported that T-ALCL has a better prognosis than non-ALCL cases. Compared to the non-T-ALCL PTCL, the 33 T/null (indetermi-nant)-ALCL patients in the Non-Hodgkin's Lymphoma Classification Project were significantly younger, less likely to have advanced-stage disease or bone marrow involvement, more likely to have favorable IPI score, and importantly, had greater survival results. The estimated 5-year overall survival for all T/null-ALCL

patients in this series was 75% and the failure-free survival was 56%, and most (81%) of these patients had been treated for curative intent with doxorubicin-con-taining regimens. Patients with ALK+ and ALK- disease had no significant differences in clinical features or survival.81 However, in a study reported by the British Columbia Cancer Agency and the University of Nebraska Medical Center, which evaluated 57 patients with systemic T/null ALCL treated with doxorubicin-containing multiagent chemotherapy protocols for curative intent, the 5-year overall survival rate was 57% (56% for 32 cases of T-ALCL and 83% for 25 cases of null-ALCL).82 ALK protein expression was an independent predictor of survival, as there was a statistically significant survival difference between the ALK+ (31 cases) and ALK- (26 cases) groups. For the ALK+ cases, the 5-year overall survival was 93% and the 5-year failure-free survival was 88%, while the 5-year overall survival was 37% and the 5-year failure-free survival was 37% for the ALK- cases. Finally, in a retrospective study involving patients with systemic T/null ALCL from multiple European institutions, the majority of whom received doxorubicin-containing regimens, showed that the ALK+ subgroup had an overall survival of 71% compared to only 15% for the ALK- subset. Ten-year disease-free survival rates were 82% for the ALK+ group and 28% for the ALK- subset.83

Studies evaluating treatment for other specific T-cell lymphoma subtypes that are non-ALCL generally have reported disappointing responses, duration of response and survival rates. T-prolymphocytic leukemia (T-PLL) is relatively resistant to conventional chemotherapy, as demonstrated by a study involving 78 patients with T-PLL.7 Thirty-two patients had received alkylating agents and nine (28%) experienced transient partial remissions (PRs). Five of 15 patients (33%) had responded to CHOP, with 1 CR lasting 3 months. However, of the 31 patients treated with pen-tostatin, 15 experienced responses (3 CRs, lasting 8, 10, and 12 months, and 12 PRs), of which 8 responses were in 15 patients treated with pentostatin as firstline therapy. Chott et al. reported results for 27 patients with intestinal T-cell lymphoma; only 7 of 14 treated with multiagent chemotherapy completed therapy. Twenty of these 27 patients have died, and 17 died within 6 months from diagnosis. The overall median survival was 4 months, and patients with stage I had better survival rates than other patients.67 In another study with 45 patients with hepatosplenic gamma/delta T-cell lymphoma, most of whom were treated with alkylating agents, CHOP or CHOP-like therapies, second- or third-generation regimens for high-grade lymphomas, and autologous or allogeneic stem cell or peripheral stem cell transplantation, CRs were obtained in five and relapses were common and early in the treatment course. Thirty-six patients were dead at the time of this study, with a median survival of only 8 months (range 0-42 months).84 However,

Matutes et al. reported results for 15 patients with ATLL who received alpha-interferon and zidovudine (AZT), 11 of whom had previously received anthracycline-containing chemotherapy regimens. Seven patients had progressive disease, and eight were in remission at the time of study completion. When starting alpha-interferon and AZT, four patients had progressive disease, eight were in partial/complete remission, and three untreated patients had active disease. PRs lasting 2+ to 44+ months (median duration 10 months) occurred in 10 (67%) patients, four (26%) had no responses, and one was not evaluable. Eight patients died 3-41 months from diagnosis. Median survival for all 15 patients was 18 months; survival for nonresponders ranged from 4 to 20 months (median 6 months), and the 6 patients with PR were alive 8-82 months from diagnosis, with 55% of all patients alive at 4 years. This study therefore suggested that this combination may improve the outcome of ATLL and help maintain responses, and should be studied in other populations.85

Standard treatments for nasal NK/T-cell lymphoma are unsatisfactory. In a retrospective analysis of Chinese patients with primary NHL of the nose and nasopharynx, many of whom received CHOP, CEOP (cyclophos-phamide, epirubicin, vincristine, and prednisone) or ProMACE-CytaBOM, with or without radiation, patients with NK/T-cell lymphoma had very poor results.86 Compared to patients with T-cell (24 patients, 21.3%) or B-cell (38 patients, 33.6%) phenotypes, those with NK/T-cell lymphoma (51 patients, 45.1%) had the highest male-to-female ratio, more frequent involvement of the nasal cavity alone, a higher risk of skin dissemination, more frequent development of hemo-phagocytic syndrome, and worse prognosis. The CR rate for NK/T-cell disease was 56%, compared to 69.6 and 76.3% for T-cell and B-cell phenotypes, respectively. The 5-year actuarial disease-free survival rates were 25.1% for NK/T-cell disease, 41.9% for T-cell phenotype, and 40.9% for B-cell phenotype. The 5-year actuarial overall survival was 31.1% for NK/T-cell phenotype, 57.7% for T-cell phenotype, and 35% for B-cell phenotype. The median overall survival was 12.5 months for NK/T-cell phenotype, 93.4 months for T-cell pheno-type, and 17 months for B-cell phenotype. In another study, investigators treated patients with localized nasal NK/T-cell lymphoma with four cycles of CHOP and involved-field radiation therapy, obtaining a response of 58% and an estimated overall 3-year survival of 59%. In fact, only 35% of patients completed the planned sequential chemoradiotherapy due to disease progression during chemotherapy. These results led to the authors' conclusion that better treatments were needed for localized nasal NK/T-cell lymphoma.87

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