Dose Intensity for Breast Cancer

Drs. Armstrong and Davidsonhave nicely reviewed the useof dose-intensive chemotherapy in the treatment of metastatic and high-riskearly-stage breast cancer, and we agree with the basic premise of the article—thatthere are no conclusive data to support the routine use of doses beyond thestandard range outside of a study setting. Bonadonna et al in 1981 demonstratedthat inferior dosing of CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar],methotrexate, fluorouracil [5-FU]) in node-positive breast cancer was equivalentto not receiving chemotherapy at all.[1] Extrapolating from this information andfrom data from other supportive studies, a number of prospective trials of moredose-intensive regimens were undertaken in the next 2 decades.

Dose Threshold

Many trials have demonstrated that increased dose intensitycould potentially result in better response rates and sometimes in prolongationof median time to progression but not in improved survival. Dose thresholds havebeen established for many active agents—doxorubicin (60 mg/m²);cyclophosphamide (600 mg/m²), paclitaxel (175 mg/m²)—as has the fact thatadequate dosing is essential (dose threshold). Escalation beyond standard dosingremains a question for study with no convincing evidence of efficacy and somedata demonstrating harm in terms of second malignancies, especially in the caseof leukemogenesis with high-dose alkylating agents.

An interesting hypothesis currently being investigated inprospective trials is that of dose density. This strategy calls for decreasingtime between treatments (ie, the time available for tumor regrowth is reduced)by using sequential administration of single agents in an intensive fashionrather than in combination. This concept has a theoretical appeal that it ishoped will translate into a survival benefit in prospective trials currentlyunderway.

Metastatic Breast Cancer

There are now five reported prospective randomized trials ofhigh-dose chemotherapy and stem cell support in advanced breast cancer. We agreewith the authors that the 1995 Bezwoda trial[2] must be discarded because ofuncertain validity, especially in light of this investigator’s admittedlyfraudulent data on the role of this therapy in high-risk breast cancer,presented in abstract form at the plenary session of ASCO 1999.[3] We are thusleft with four randomized trials in the metastatic setting on which to comment.

The French PEGASE 4 trial although small (61 patientsrandomized), did show a trend toward improvement of median overall survival forthe high-dose arm, but that trend was not statistically significant.[4] Theresults suggested, however, that this therapeutic approach holds promise. ThePhiladelphia Intergroup study, did not show any incremental benefit forhigh-dose chemotherapy in 3-year overall, or relapse-free survival.[5] Criticismregarding the number of eligible patients actually randomized (199 patients inthe analysis) is unwarranted. This was a study of two postremission approaches.Only 310 patients responded to induction therapy and thus were eligible forrandomization; the majority were thus randomized.

We are unsure of how to interpret the prolonged median survivalof the group receiving high-dose chemotherapy at second recurrence (3.2 years)rather than at first complete remission (2.3 years) in the Duke Crossover study(98 patients).[6] The only patients randomized were those in complete remission,which represented approximately 25% of the original 400 patients entered intothe study. We await final analysis and publication of the complete manuscript tointerpret these data further.

Investigators at Duke also looked at high-dose chemotherapy in69 patients with breast cancer that had metastasized to a limited number of bonesites.[7] They again examined the role of delayed vs immediate vs high-dosechemotherapy after standard chemotherapy. The difference in progression-freesurvival (1.0 vs 0.91 years) has been reported as significantly favoringhigh-dose chemotherapy, although one could well question the clinicalsignificance; indeed, median overall survivals were approximately the same (2.01vs 1.8 years) at 4.9 years median follow-up.

Thus, despite more than 10 years of investigation with over5,000 patients treated and a collective randomized trial experience in over 400patients, there is no definitive evidence of the therapeutic efficacy ofhigh-dose chemotherapy in metastatic breast cancer. A number of other randomizedtrials in metastatic breast cancer remain to be reported. We believe that untilproof of principle is demonstrated in the adjuvant high-risk breast cancersetting, where treatment of micrometastatic disease is the goal, use of thismodality in metastatic breast cancer should be limited to innovative clinicalinvestigations.

High-Risk Breast Cancer

Turning to early-stage breast cancer and high-dose chemotherapy,there are six randomized published trials, one of which is the strongly positivebut discredited South African study mentioned earlier. A Dutch pilot trialexamined the role of high-dose chemotherapy (with cyclophosphamide, thiotepa[Thioplex], and carboplatin [Paraplatin]) in 97 patients with a positiveinfraclavicular lymph node biopsy who had responded to initial treatment withpreoperative FEC (fluorouracil, epirubicin [Ellence], cyclophosphamide).[8] At amedian follow-up of 49 months there was no difference in progression-free oroverall survival between the two arms.

The same group has now enrolled 885 patients with four or morepositive axillary lymph nodes and examined the same high-dose chemotherapyregimen used in the pilot study in place of a fifth cycle of FEC.[9] A plannedsubgroup analysis of the first 284 patients showed a benefit in 3-year overalland relapse-free survival. The results are promising, but the final results arenot expected until 2002. Meanwhile, enthusiasm must be tempered by the otherstudies reported to date.

An M. D. Anderson trial in 78 patients with 10 or more positiveaxillary nodes showed no benefit for the high-dose arm at a median follow-up of6.5 years.[10] A 525-patient trialby the Scandinavian Breast Cancer Study Group reported no differencein relapse-free or overall survival ata 2-year median follow-up.[11] ACALGB Intergroup trial in 874 women with 10 or more involved lymph nodes foundsimilar event-free and overall survival data at a median follow-up of 37 monthsand, so far, does not favor high-dose therapy, although a trend toward reducedrelapse-free survival is evident.[12]

Comments and Recommendations

What can we conclude? Unfortunately, most patients withmetastatic breast cancer still relapse and die within 3 years, and bettertherapeutic interventions are needed. High-dose chemotherapy and stem cellrescue does allow for increased dose density, intensity, and response. Themorbidity, mortality, and cost of high-dose chemotherapy with stem cell rescuehas decreased substantially over the past decade, and quality of life does notdecline substantially after transplant. These observations support further studyof this approach.

However, the incorporation of one cycle of high-dosechemotherapy and stem cell rescue into the treatment of metastatic breast cancerhas so far been associated with no difference in overall or relapse-freesurvival. Follow-up of these studies is adequate given the short natural historyof metastatic breast cancer, and these results are unlikely to change withlonger observation. The design of the reported studies reflects current practicebut such treatment may be suboptimal; promising designs such as double/tandemtransplants, stem cell purging, immunotherapy, and so forth are worthy of activeinvestigation.

The incorporation of high-dose chemotherapy with stem cellrescue into the treatment of high-risk breast cancer, however, has been muchmore successful. All studies show a greater than 60% to 70% 3-year relapse-freesurvival, and this is as good as the results obtained with any other treatmentfor high-risk breast cancer. The follow-up periods for these studies are not yetlong enough to determine benefit in light of the long natural history ofhigh-risk breast cancer. We also need to await mature results of other ongoingtrials in high-risk breast cancer for final answers.

We still believe that high-dose therapy and stem cell rescuewill ultimately be shown to improve outcome in breast cancer. We agree, however,that up to this point this has not been demonstrated, and use of this modalityshould be limited to well-designed clinical trials. These studies should besupported by physicians, patients, and third-party payers. The past history ofinadequate support for these trials has led to delayed information, to thedetriment of us all. That said, we hope and believe that the next generation oftherapeutic interventions will be even more effective and make the entire matterof high-dose chemotherapy and stem cell transplant for breast cancer moot.

References:

1. Bondadonna G, Valagussa P: Dose-response effect of adjuvantchemotherapy in breast cancer. N Engl J Med 304:10-15, 1981.

2. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy withhematopoietic rescue as primary treatment for metastatic breast cancer: Arandomized trial. J Clin Oncol 13:2483-2489, 1995.

3. Bezwoda WR: Randomized, controlled trial of high-dosechemotherapy (HD-CNVp vs standard-dose (CAF) chemotherapy for high-risk,surgically treated, primary breast cancer (abstract 4). Proc Am Soc Clin Oncol18:2a, 1999.

4. Lotz JP, Cure H, Janvier M, et al: High-dose chemotherapy(HD-CT) with hematopoietic stem cells transplantation (HSCT) for metastaticcancer (MBC): Result of the French protocol PEGASE 04 (abstract 161). Proc AmSoc Clin Oncol 18:43a, 1999.

5. Stadtmauer EA, O’Neill A, Goldstein LJ, et al:Conventional-dose chemotherapy compared with high-dose chemotherapy plusautologous hematopoietic stem-cell transplantation for metastatic breast cancer.N Engl J Med 342:1069-1076, 2000.

6. Peters WP, Jones RB, Vredenburgh J, et al: A largeprospective randomized trial of high-dose combination alkylating agents (CPB)with autologous cellular support (ABMS) as consolidation for patients withmetastatic breast cancer achieving complete remission after intensivedoxorubicin-based induction therapy (AFM) (abstract 149). Pro Am Soc Clin Oncol15:121, 1996.

7. Madan B, Broadwater B, Rubin P, et al: Improved survival withconsolidation high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB)compared with observation in women with metastatic breast cancer (MBC) and onlybone metastatics treated with induction Adriamycin, 5-fluorouracil, andmethotrexate (AFM): A phase III prospective randomized comparative trial(abstract 184). Proc Am Soc Clin Oncol 19:48a, 2000.

8. Rodenhuis S, Richel DJ, van der Waal E, et al: Randomizedtrial of high- dose chemotherapy and haematopoietic progenitor-cell support inoperable breast cancer with extensive axillary lymph node involvement. Lancet352:515-521, 1998.

9. Rodenhuis S, Bontenbal M, Beex L, et al: Randomized phraseIII study of high-dose chemotherapy with cyclophosphamide, thiotepa, andcarboplatin in operable breast cancer with four or more axillary lymph nodes(abstract 286). Proc Am Soc Oncol 19:74a, 2000.

10. Hortobagyi GN, Buzdar AU, Thierault L, et al: Randomizedtrial of high- dose chemotherapy and blood cell autograph for high-risk primarybreast carcinoma. J Natl Cancer Inst 92:225-233, 2000.

11. The Scandinavian Breast Cancer Study Group 9401: Resultsfrom a randomized adjuvant breast cancer study with high-dose chemotherapy withhigh-dose chemotherapy with CTC supported by autologous bone marrow stem cell vsdose escalated and tailored FEC (abstract 3). Proc Am Soc Clin Oncol 18:2a,1999.

12. Peters W, Rosner G, Vredenburgh J, et al: A prospective,randomized comparison of two doses of combination alkylating agents (AA) asconsolidation after CAF in high-risk primary breast cancer involving 10 or moreaxillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/NCICMA-13 (abstract 2). Proc Am Soc Clin Oncol 18:1a, 1999.