Cochrane Clinical Answers - Fulltext - In women with early poor prognosis breast cancer, how does high-dose chemotherapy plus autologous bone marrow or stem cell transplantation compare with conventional chemotherapy?

Question:In women with early poor prognosis breast cancer, how does high-dose chemotherapy plus autologous bone marrow or stem cell transplantation compare with conventional chemotherapy?

Clinical Answer:

In women with early poor prognosis breast cancer, high-dose chemotherapy increases treatment-related mortality and is associated with little or no benefit in survival.

There is high-quality evidence that high-dose chemotherapy plus autologous bone marrow or stem cell transplantation does not increase the likelihood of overall survival at any stage of follow-up, compared with standard chemotherapy. High-dose chemotherapy appears to improve the likelihood of event-free survival at three years, but this effect is no longer apparent at longer duration of follow-up.

Treatment-related deaths are more frequent with the high-dose regimen and non-fatal morbidity is also more common and more severe in women treated with high-dose chemotherapy, compared with standard chemotherapy.

On average, women in the high-dose group report worse quality-of-life scores immediately after treatment, although differences tend to disappear over time.

Full outcome data is detailed below:

1.High-dose chemotherapy versus standard chemotherapy

  • Population, Intervention, Comparator

    Population:

    Women (median age range 43 to 47 years) with early poor prognosis breast cancer, having evidence of multiple axillary lymph node involvement and no evidence of distant metastasis. Specific prognostic factors, such as number of positive lymph nodes varied greatly across trials. Most women began chemotherapy soon after full or partial mastectomy and axillary node dissection. Same initial chemotherapy was given to most women: three to eight cycles of cyclophosphamide with anthracycline (doxorubicin or epirubicin) and fluorouracil (8 trials) or multiple cycles of cyclophosphamide and epirubicin only (2 trials) or four cycles of doxorubicin alone (1 trial). All women received a course of radiotherapy after chemotherapy

    Intervention:

    High-dose chemotherapy: Granulocyte colony-stimulating factor (GCSF) to stimulate the production of white cells which were then harvested for later transplantation was given during initial chemotherapy. After this, one or two cycles of high-dose chemotherapy: cyclophosphamide with thiotepa or etoposide or carmustine, with or without a platinum-based drug (cisplatin or carboplatin) or mitoxantrone

    Comparator:

    Standard chemotherapy: No further chemotherapy given after initial phase (5 trials); continuation of the initial chemotherapy (2 trials); standard course of a different chemotherapy (cyclophosphamide, methotrexate and fluorouracil (CMF); 1 trial); "intermediate level" version of the high-dose therapy along with a course of GCSF to stimulate white cell production (1 trial); two combination therapies in sequence (2 trials) or sequential dose-dense and dose-escalated chemotherapy (1 trial)

  • OUTCOME 1.1: Overall survival

    Narrative result:

    There was no evidence of a difference between groups at any time point. Click below for full details.

    Reference:
    Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.1.1: Overall survival - [subgroup: 3-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 1/3 (33%) of the studies failed to report adequate allocation concealment, none reported adequate blinding of participants/carers/outcome assessors but all had low numbers of withdrawals.

      Narrative result:

      Three RCTs with 795 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.02, 95% CI 0.95 to 1.10).

      Forest plot from Cochrane Review

      Absolute effect:

      765 per 1000 women (95% CI 713 to 821) with high-dose chemo compared with 748 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.1.2: Overall survival - [subgroup: 5-year follow-up]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

      Narrative result:

      Eight RCTs with 3566 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.00, 95% CI 0.96 to 1.04).

      Forest plot from Cochrane Review

      Absolute effect:

      672 per 1000 women (95% CI 645 to 698) with high-dose chemo compared with 672 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.1.3: Overall survival - [subgroup: 6-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study failed to report adequate allocation concealment, did not report adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 511 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 0.94, 95% CI 0.81 to 1.08).

      Forest plot from Cochrane Review

      Absolute effect:

      579 per 1000 women (95% CI 502 to 667) with high-dose chemo compared with 619 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.1.4: Overall survival - [subgroup: 8-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study reported adequate allocation concealment, did not report adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 344 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.17, 95% CI 0.95 to 1.43).

      Forest plot from Cochrane Review

      Absolute effect:

      561 per 1000 women (95% CI 457 to 688) with high-dose chemo compared with 480 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.1.5: Overall survival - [subgroup: 12-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study reported adequate allocation concealment, did not report adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 382 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.18, 95% CI 0.99 to 1.42).

      Forest plot from Cochrane Review

      Absolute effect:

      600 per 1000 women (95% CI 501 to 719) with high-dose chemo compared with 508 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
  • OUTCOME 1.2: Event-free survival

    Narrative result:

    At three-year follow-up, event-free survival was higher with high-dose chemotherapy compared with standard chemotherapy but there was no obvious difference between groups at later time points. Click below for full details.

    Reference:
    Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.2.1: Event-free survival - [subgroup: 3-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 1/3 (33%) of the studies failed to report adequate allocation concealment, none reported adequate blinding of participants/carers/outcome assessors but all had low numbers of withdrawals.

      Narrative result:

      Three RCTs with 795 participants found that event-free survival was higher with high-dose chemotherapy compared with standard chemotherapy.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of high-dose chemotherapy (RR 1.19, 95% CI 1.06 to 1.34).

      Forest plot from Cochrane Review

      Absolute effect:

      642 per 1000 women (95% CI 572 to 721) with high-dose chemo compared with 540 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.2.2: Event-free survival - [subgroup: 5-year follow-up]
      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

      Narrative result:

      Eight RCTs with 3566 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.04, 95% CI 0.99 to 1.10).

      Forest plot from Cochrane Review

      Absolute effect:

      601 per 1000 women (95% CI 572 to 633) with high-dose chemo compared with 578 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.2.3: Event-free survival - [subgroup: 6-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study did not report adequate allocation concealment, adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 511 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.04, 95% CI 0.87 to 1.24).

      Forest plot from Cochrane Review

      Absolute effect:

      488 per 1000 women (95% CI 407 to 585) with high-dose chemo compared with 471 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.2.4: Event-free survival - [subgroup: 8-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study reported adequate allocation concealment, did not report adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 344 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.27, 95% CI 0.99 to 1.64).

      Forest plot from Cochrane Review

      Absolute effect:

      468 per 1000 women (95% CI 364 to 603) with high-dose chemo compared with 368 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • Subgroup analysis 1.2.5: Event-free survival - [subgroup: 12-year follow-up]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The study reported adequate allocation concealment, did not report adequate blinding of participants/carers/outcome assessors but had low numbers of withdrawals.

      Narrative result:

      One RCT with 382 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.18, 95% CI 0.95 to 1.45).

      Forest plot from Cochrane Review

      Absolute effect:

      519 per 1000 women (95% CI 421 to 640) with high-dose chemo compared with 442 per 1000 women with standard chemotherapy.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
  • OUTCOME 1.3: Treatment-related mortality (follow-up from 3 to 12 years)

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

    Narrative result:

    14 RCTs with 5600 participants found that treatment-related mortality was higher with high-dose chemotherapy compared with standard chemo. Most deaths occurred in one trial, caused by acute infection, pulmonary toxicity or renal failure (hemolytic-uremic syndrome). Most deaths occurred within the first year of treatment.

    Relative effect or mean difference:

    There was a statistically significant difference between groups, in favor of standard chemotherapy (RR 7.97, 95% CI 3.99 to 15.92).

    Forest plot from Cochrane Review

    Absolute effect:

    14 per 1000 women (95% CI 7 to 28) with high-dose chemo compared with 2 per 1000 women with standard chemotherapy.

    Reference:
    Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
    • OUTCOME 1.4: Toxicity

      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 2/7 (29%) of the studies failed to report adequate allocation concealment, none reported adequate blinding of participants/carers/outcome assessors but all had low numbers of withdrawals.

      Narrative result:

      Seven trials reported higher toxicity (neutropenia, often accompanied by fever and infection) in women receiving high-dose chemotherapy. Other adverse effects such as fatigue, vomiting, mucositis and diarrhea were also more common and more severe with high-dose chemotherapy, which could also induce menopause. Organ toxicities (cardiac, pulmonary, renal, hepatic, bladder, skin and neurological complications) affected more women in the high-dose arms but were not severe and were reversible.

      Relative effect or mean difference:

      Data were reported narratively.

      Reference:
      Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
      • OUTCOME 1.5: Secondary cancers at 4 to 9-year median follow-up

        Quality of the evidence:

        The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was high quality. See Summary of findings from Cochrane review

        Narrative result:

        Seven RCTs with 3423 participants found no statistically significant difference between groups. Subgroup analysis by time of follow-up (4 to 5 years, 6, 7 or 8-9 years) found similar results to the main analysis.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (RR 1.25, 95% CI 0.90 to 1.73).

        Forest plot from Cochrane Review

        Absolute effect:

        31 per 1000 women (95% CI 23 to 43) with high-dose chemo compared with 25 per 1000 women with standard chemotherapy.

        Reference:
        Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]
        • OUTCOME 1.6: Quality of life

          Quality of the evidence:

          The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 2/6 (33%) of the studies failed to report adequate allocation concealment, none reported adequate blinding of participants/carers/outcome assessors but all had low numbers of withdrawals.

          Narrative result:

          Six trials reported this outcome using different instruments. Two of them found no statistically significant difference between groups; two trials found worse quality of life in the high-dose group at three weeks to three months but the difference became minimal at one year in one of them. In one trial quality of life was worse after chemotherapy but there was no statistically significant difference between groups at six months. In another trial there was a strong deterioration in quality of life during treatment but three months after completion of radiotherapy there was no difference between groups.

          Relative effect or mean difference:

          Data were reported narratively.

          Reference:
          Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]

          Additional Information:

          DOI

          10.1002/cca.1433

          Publication Dates

          1. Published Online: 12 OCT 2016

          CCA derived from

          Farquhar C, Marjoribanks J, Lethaby A, Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD003139. DOI: 10.1002/14651858.CD003139.pub3. [Review search date: October 2015]

          How to Cite

          In women with early poor prognosis breast cancer, how does high-dose chemotherapy plus autologous bone marrow or stem cell transplantation compare with conventional chemotherapy? Simone Mocellin (MD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2012. DOI: 10.1002/cca.1433.

          Further Information

          • CCA Associate editor: Simone Mocellin (MD), Physician, University of Padova, Italy.
          • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.