Doxil®--the first FDA-approved nano-drug: lessons learned.

Summary Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14. Methods 1222 elderly patients (aged 61–80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243. Findings 3-year event-free survival was 47·2% after six cycles of CHOP-14 (95% CI 41·2–53·3), 53·0% (47·0–59·1) after eight cycles of CHOP-14, 66·5% (60·9–72·0) after six cycles of R-CHOP-14, and 63·1% (57·4–68·8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5·8% (−2·8–14·4) for eight cycles of CHOP-14, 19·3% (11·1–27·5) for six cycles of R-CHOP-14, and 15·9% (7·6–24·2) for eight cycles of R-CHOP-14. 3-year overall survival was 67·7% (62·0–73·5) for six cycles of CHOP-14, 66·0% (60·1–71·9) for eight cycles of CHOP-14, 78·1% (73·2–83·0) for six cycles of R-CHOP-14, and 72·5% (67·1–77·9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by −1·7% (−10·0–6·6) after eight cycles of CHOP-14, 10·4% (2·8–18·0) after six cycles of R-CHOP-14, and 4·8% (−3·1–12·7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0·76 [0·60–0·95], p=0·0172; six cycles of R-CHOP-14: RR 0·51 [0·40–0·65], p Interpretation Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(08)70002-0.pdf

Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or follicular B-cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in combination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not been reached after a median observation time of 29 + months. Twenty-eight of 38 assessable patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attributable to CHOP were alopecia (38 pati...

Treatment of Patients With Low-Grade B-Cell Lymphoma With the Combination of Chimeric Anti-CD20 Monoclonal Antibody and CHOP Chemotherapy

Purpose For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). Methods We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with “B” symptoms or bulky [> 10 cm] disease) DLBCL. Results A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P =...

Introduction of Combined CHOP Plus Rituximab Therapy Dramatically Improved Outcome of Diffuse Large B-Cell Lymphoma in British Columbia

Purpose For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). Methods We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with B symptoms or bulky [> 10 cm] disease) DLBCL. Results A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% Cl, 0.39 to 0.81; P =.002) and overall survival (risk ratio, 0.40; 95% Cl, 0.27 to 0.61, P <.0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% Cl, 0.41 to 0.85; P =.005) and overall survival (risk ratio, 0.43; 95% Cl, 0.29 to 0.66; P <.001). The benefit of treatment in the postrituximab era was present regardless of age. Conclusion The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.

Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia

Combination chemotherapy with CHOP (cyclophosphamide, Adriamycin, vin-cristine, and prednisone) and HOP (Adriamycin, vincristine, and prednisone) was used as treatment for patients with pathologically staged, advanced non-Hodgkin's lymphoma. Among 204 evaluable patients treated on CHOP there were 71% complete remissions with 92% overall responses. Among the 216 evaluable patients on HOP there were 61% complete remissions and 88% responses. Complete remission rates among patients with histiocytic lymphoma were comparable to those of patients with lymphocytic disease. Patients with nodular lymphoma had higher rates of complete remission than their counterparts with diffuse lymphoma. This was noted with both CHOP (78% vs. 67%) and HOP (67% vs. 60%) induction therapy. Rapid responses were common, as more than 14% of complete remissions and 66% of overall responses were achieved with the first course of treatment. Patients in complete remission have been maintained with either cyclophosphamide, vincristine, and prednisone (COP) or arabinosyl cytosine, vincristine, and prednisone (OAP). After 1 year, 86% of patients on COP and 80% on OAP are projected to be free of disease.

Ronald Stephens

Papers

Hydroxyldaunomycin (adriamycin) combination chemotherapy in malignant lymphoma