Dose density and dose intensity: where does CHOP go from here?

C. S. Portlock

Attending Physician, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room H-819, New York, NY 10021, USA (E-mail: portlocc@mskcc.org)

Non-myeloablative chemotherapy regimens have not been fully explored in the treatment of aggressive non-Hodgkin’s lymphomas [1]. Two important concepts in the development of new chemotherapy regimens are dose intensity [dose of effective drug administered per unit time (mg/m2/week), calculated per week even when the agent is administered once every 3 weeks as in CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)] and dose density (the frequency of effective drug dose administered) [2, 3]. In aggressive non-Hodgkin’s lymphomas, myeloablative dose intensity has been successfully established in the autologous stem cell salvage therapy of chemosensitive relapse [4]. In the upfront setting, however, it has been more difficult to demonstrate the role of dose intensity for two reasons: (i) conventional CHOP chemotherapy is potentially curative with an excellent toxicity profile; and (ii) myeloablative therapy is cumbersome and limited to younger patients, and rapidly refractory tumor may limit its application.

With the availability of growth factor support, maximally tolerated non-myeloablative doxorubicin-based regimens have been developed. The dose-intensity approach is simply to escalate CHOP while maintaining a q3 week schedule. In a rapidly growing lymphoma, this strategy may deliver a higher dose per unit time compared with CHOP, but escape and regrowth of marginally sensitive cells will remain a problem. Another chemotherapy manoeuver is to administer standard CHOP on a shortened schedule, every 2 weeks. This dose-dense therapy takes advantage of the frequency of effective drug exposure, thus preventing susceptible cell regrowth.

In this issue of Annals of Oncology, Itoh et al. [5] compare a dose-intense CHOP regimen [cyclophosphamide (C) 1500 mg/m2, doxorubicin (H) 50 mg/m2], administered on a standard 3 week schedule, with a dose-dense standard CHOP regimen (C = 750 mg/m2; H = 50 mg/m2), administered every 2 weeks. Balzarotti et al. [6] test a CHOP regimen that is both dose-intense and dose-dense, escalating the cyclophosphamide dose in cohorts (starting at 1750 mg/m2 and increasing by 250 mg/m2) while maintaining H (doxorubicin) at 75 mg/m2 every 2 weeks. So far, neither group has prospectively compared their intensified regimen with standard CHOP, which is delivered every 3 weeks.

Key study characteristics that might influence the outcome of these reports ([5] versus [6], respectively) include: (i) median age (61 years compared with 48 years); (ii) histology (more T-cell compared with more low-grade histology); (iii) International Prognostic Index (IPI) risk groups (3, 4 compared with 1, 2, 3, 4); (iv) consolidative treatment post-CHOP regimen (none compared with radiotherapy or stem cell transplant); (v) response assessment criteria (nuclear imaging compared with none); and (vi) actual rather than projected dose reporting? (‘no’ compared with ‘yes’).

Both studies demonstrate that severe infections associated with neutropenia and non-hematologic toxicities become dose-limiting with the intensification of CHOP regimens. Balzarotti et al. [6] provide actual dose intensity (ADI) data, rather than projected dosing (PDI) only, demonstrating that planned increases in dosing could not be achieved, and that at higher planned dosing the actual dose delivered was in fact decreased, not increased. For example, at planned dosing of C = 1750 mg/m2 and H = 75 mg/m2, ADI was 1.69 for intensified q2 week CHOP (projected 1.87), as compared with standard CHOP q3 weeks (1.0). However, at C = 2250 mg/m2 and H = 75 mg/m2, ADI was 1.62 for intensified CHOP (projected 2.18) compared with standard CHOP (1.0).

The response and remission data for both trials are disappointing, although they are preliminary results. Complete response (CR) plus uncertain complete response is 51–60% with freedom from progression (FFP) of 31–43% at 3 years for Itoh et al. in IPI 3, 4 patients. For Balzarotti et al., CR is 74% for all risk groups with FFP of 58% at 12 months in the IPI 3, 4 categories. Although marginally better than historical CHOP data, none of the dose-escalated regimens resulted in a convincing improvement in CR or FFP.

Does this mean that non-myeloablative dose-intensity and/or dose-density strategies are dead concepts in the management of aggressive non-Hodgkin’s lymphoma? Not yet. Optimal dosing of standard CHOP is essential, and as Balzarotti et al. have shown here, planned escalating doses may not result in higher actual doses being administered. Results from the two studies reported in this issue do raise a provocative question: can all CHOP chemotherapy-susceptible lymphoma cells be killed simply by optimizing the dose and schedule of standard CHOP?

If non-myeloablative CHOP dose escalation has any role to play, the increment of increased curability is probably small, based on these two studies and those of others. In the future, targeted agents that may overcome CHOP drug resistance through alternative mechanisms of action will be increasingly important. Rituximab (anti-CD20 monoclonal antibody) plus CHOP is one such example, and the future of these strategies appears bright [7]. Nevertheless, we must bear in mind that it is combination chemotherapy that has achieved consistent curative outcomes in aggressive lymphomas and that targeted therapies have not yet passed this rigorous hurdle. As both Itoh et al. and Balzarotti et al. have emphasized, careful prospective testing of dose-dense and/or dose-intense regimens will be needed to prove that these regimens are better than standard CHOP. Importantly, however, even a small improvement in outcome would be anticipated to result in a definite incremental increase in curative potential.

C. S. Portlock

Attending Physician, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room H-819, New York, NY 10021, USA (E-mail: portlocc@mskcc.org)

References

1. Santoro A, Balzaraotti M, Castagna L. Intensified CHOP in non-Hodgkin’s lymphoma: what we know and what we need to know. Ann Oncol 1999; 10: 875–876.[ISI][Medline]

2. Meyer RM, Hryniuk WM, Goodyear MD. The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin’s lymphoma. J Clin Oncol 1991; 9: 339–347.[Abstract]

3. Hudis C. Dose-dense chemotherapy for breast cancer: the story so far. Br J Cancer 2000; 82: 1897–1899.[ISI][Medline]

4. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–1545.[Abstract/Free Full Text]

5. Itoh K, Ohtsu T, Fukuda H et al. Randomized phase II study of biweekly CHOP and dose-escalated CHOP with prophylactic use of lenograstim (glycosylated G-CSF) in aggressive non-Hodgkin’s lymphoma: Japan Clinical Oncology Group Study 9505. Ann Oncol 2002; 13: 1347–1355.[Abstract/Free Full Text]

6. Balzarotti M, Spina M, Sarina B et al. Intensified CHOP regimen in aggressive lymphomas: maximal dose intensity and dose density of doxorubicin and cyclophosphamide. Ann Oncol 2002; 13: 1341–1346.[Abstract/Free Full Text]

7. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242.[Abstract/Free Full Text]





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