Cancer Treatment Today

Lay Summary: Metronomic chemotherapy, small doses of cehmo for prolonged time, is under intensive study.

SWOG 0012 was a precursor for an ongoing adjuvant trial (SWOG 0221) that is looking at a novel approach to the administration of chemotherapy based on previous studies showing that metronomic dosing can overcome chemotherapy resistance in a variety of model systems.

SWOG 0012 compared standard chemotherapy to the metronomic approach in the neoadjuvant setting.13 The primary endpoint was pCR. A total of 372 patients with LABC or infl ammatory breast cancer (IBC) were enrolled in the study, with 265 evaluable for primary outcome. Metronomic chemotherapy consisted of doxorubicin 24 mg/m2/week and oral cyclophosphamide 60 mg/m2/day for 15 weeks, with weekly granulocyte colony-stimulating factor (G-CSF) support. In previous trials, patients who did not receive growth factors had an increase in dermatitis as well as hematologic toxicity, which was ameliorated with G-CSF support. The control arm received every-3-week doxorubicin/cyclophosphamide at standard doses for 5 doses (as opposed to the standard 4). Both treatment groups then received standard weekly paclitaxel for 12 weeks. Approximately 30% of the patients had IBC, so this was a very locally advanced disease group. The toxicity between the arms was similar to that seen in prior studies (13% grade 3/4 hand-foot syndrome [HFS] associated with metronomic dosing vs. 0 with standard treatment), but neutropenia was markedly reduced because of the G-CSF (16% with metronomic dosing vs. 47% with standard treatment). There was very minimal difference in reports of febrile neutropenia.

The response results are quite striking. There was a statistically significant difference in pCR rate at the primary site of 19% in the standard arm compared to 31% in the metronomic arm. This is one of the highest pCR rates reported in IBC. Considering patients who had both pCR and node negativity, the difference is also striking: 15% in the standard arm compared to 26% with metronomic-dose chemotherapy. The metronomic regimen is clearly quite tolerable, HFS being the major toxicity, with fewer hematologic side effects and what appears to be improved efficacy compared to standard dosing. This study demonstrates that occasionally data from preclinical models can inform the clinical setting with very positive results. The very encouraging clinical results support enrollment to SWOG 0221, an ongoing adjuvant trial comparing dose-dense chemotherapy to the metronomic approach. This is a phase III Trial of Continuous Schedule AC + G Vs. Q 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Therapy in Node-Positive or High -Risk Node Negative Breast Cance The arms are:
Arm 1: Patients receive Adriamycin and Cytoxan IV every two weeks for 12 weeks (6 cycles). This is followed by Paclitaxel every two weeks for 12 weeks. On the day after each chemotherapy, a dose of sub-q Pegfilgrastim is given.

Arm 2: Patients receive Adriamycin weekly for 15 weeks. They take oral Cytoxan daily for 15 weeks. During this period, patients will give themselves a daily sub-q injection of Filgrastim, except on days they receive Adriamycin. This is followed by Paclitaxel every two weeks for 12 weeks. On the day after each Paclitaxel dose, patients receive a sub-q injection of Pegfilgrastim.

Arm 3: Patients receive Adriamycin and Cytoxan (AC) IV every two weeks for 12 weeks (6 cycles). On the day after each dose of AC, a dose of sub-q Pegfilgrastim is given. This is followed by Paclitaxel given weekly for 12 weeks.

Arm 4: Patients receive Adriamycin weekly for 15 weeks. They take oral Cytoxan daily for 15 weeks. During this period, patients will give themselves a daily sub-q injection of Filgrastim, except on days they receive Adriamycin. This is followed by Paclitaxel given weekly for 12 weeks.

Arm one is currenlty the only standard of care arm.

Obviously, this is an experimental approach and the treatment offfered on this trial, unless it is on arm 1, is considered experimental under the plan’s defintion. The assigned Arm is not known or we have not been advised. IF ti turns out to be Arm 1, the case can be re-reviewed or appealed.

Ellis GK, Livingston RB, Gralow JR, et al. Dose-dense anthracycline-based chemotherapy for node-positive breast cancer. J Clin Oncol 2002; 20:3637-43. Ellis GK, Barlow WE, Russell CA, et al. SWOG 0012, a randomized phase III comparison of standard doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T) versus weekly doxorubicin and daily oral cyclophosphamide plus G-CSF (G) followed by weekly paclitaxel as neoadjuvant therapy for infl ammatory and locally advanced breast cancer. J Clin Oncol 2006; 24(suppl):933s (abstract LBA537). nccn.org, breast cancer