- Email: [email protected]
Optimising initial treatment for follicular lymphoma
Reflection and Reaction
been shown to downregulate VEGF, decrease the amount of hypoxia in the prostate, and normalise vasculature.10 Vergis and colleagues have defined an appropriate population in which antihypoxic treatments should be studied. Bevacizumab, a VEGF sequestrant, has been assessed in patients with hormone-resistant prostate cancer and has shown encouraging findings in phase II trials. However, VEGF expression is only one aspect of hypoxia and a host of new anti-HIF-1-alpha drugs are in development. An appropriate setting for testing might be to administer drugs in the presurgical neoadjuvant setting and monitor their effect on hypoxic markers in prostatectomy specimens. The targeting of hypoxic cells has fallen out of favour in the past decade. Perhaps with the combination of effective biological interventions and appropriate patient stratification based upon Vergis’s data, antihypoxia drugs will once again enter the limelight. Yaacov Richard Lawrence, Adam P Dicker* Department of Radiation Oncology, Division of Experimental Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA [email protected]
The authors declared no conflicts of interest. YRL is supported by a grant from the “American Physicians’ Fellowship for Medicine in Israel”. 1 2
3 4
5
6
7
8
9
10
Alper T, Howard-Flanders P. Role of oxygen in modifying the radiosensitivity of E. coli B. Nature 1956; 178: 978–79. Bindra RS, Schaffer PJ, Meng A, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004; 24: 8504–18. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007; 26: 225–39. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447–54. Movsas B, Chapman JD, Greenberg RE, et al. Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2) study. Cancer 2000; 89: 2018–24. Movsas B, Chapman JD, Hanlon AL, et al. Hypoxic prostate/muscle pO2 ratio predicts for biochemical failure in patients with prostate cancer: preliminary findings. Urology 2002; 60: 634–39. Vergis R, Corbishley CM, Norman AR, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 2008; 9: 342–51. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60: 1541–45. Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601. Woodward WA, Wachsberger P, Burd R, Dicker AP. Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade. Prostate Cancer Prostatic Dis 2005; 8: 127–32.
Optimising initial treatment for follicular lymphoma The management of follicular lymphoma is not straightforward. Despite therapeutic advances and an improved understanding of disease biology, most efforts have resulted in promising, but only modest, improvements in overall survival. The frequently cited long clinical course misrepresents the difficulty of a relapsing disease, a continuous risk of transformation to more aggressive histologies, and extremes of survival where most patients will die either as a direct result of the disease or as a complication of treatment. The efficacy of external-beam radiotherapy in follicular lymphoma has been recognised for many decades, and, for the small number of patients who present with earlystage disease, durable remissions, and in some cases cures, can be achieved with this treatment modality. Most patients will, however, present at an advanced stage, and, for those who are asymptomatic or not compromised by the disease, there is a large amount of evidence of no improvement in survival after early http://oncology.thelancet.com Vol 9 April 2008
intervention with cytotoxic treatment; the best course of action for these patients is to reserve the use of such treatment for later in the disease course. However, such a policy of watchful waiting is nihilistic and is rightly being rechallenged in the era of rituximab, a monoclonal antibody directed against the CD20 antigen expressed on most malignant B cells. For patients who present with advanced-stage disease and who are in need of immediate treatment, because of symptoms or organ compromise, the choices for firstline treatment are broad, and, as evidenced by the US National Lymphocare study,1 there is clear diversity in the treatments used in clinical practice. In this setting, four randomised studies have shown that the addition of rituximab to conventional first-line chemotherapy regimens not only increases the overall number of responses, complete responses, and the duration of response, but also affects overall survival.2–5 Findings for the experimental groups in each of these phase III studies
See Articles page 352
309
John Cole/Science Photo Library
Reflection and Reaction
Patient receiving mitoxantrone, which can be augmented with radioimmunoconjugates
are impressive, with responses noted in 81–96% of patients, of which 20–75% had a complete response. The current diversity in clinical practice, therefore, does not arise from the inclusion of rituximab in initial treatment, but from the choice of which cytotoxic drugs should be used in combination with rituximab to achieve the best chance of a good-quality durable remission with acceptable toxic effects. In the USA, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is currently the regimen of choice.1 The radioimmunoconjugates iodine-131 (131I)-tositumomab and yttrium-90 (90Y)-ibritumomab tiuxetan consist of CD20-targeted monoclonal antibodies conjugated to a radionuclide. Therefore, these radiolabelled drugs harness the sensitivity of follicular lymphoma to both immunotherapy and radiotherapy, and both have shown significant activity in relapsed disease.6,7 In untreated patients, provocative data on the single-agent activity of 131I-tositumomab have been reported, showing responses in 95% (72 of 76 patients) of patients.8 131I-tositumomab can be administered over a single week and is free of many of the conventional non-haematological toxic effects of chemotherapy.8 However, the patients included in this study were a select group from the population of patients with follicular lymphoma because, not least, those with more than 25% bone-marrow infiltration were excluded due to the risk of increased myelotoxic effects. In this issue of The Lancet Oncology, Zinzani and co-workers9 report the findings of the FLUMIZ 310
(FLUdarabine, MItoxantrone, Zevalin) phase II multicentre trial, in which 57 patients with previously untreated follicular lymphoma received six cycles of fludarabine and mitoxantrone followed by 90Y-ibritumomab tiuxetan after documentation of a chemotherapy-induced response. The use of such a multimodal approach is an attractive option, because initial tumour debulking with chemotherapy can result in an optimum environment for successful radioimmunotherapy as a result of the low disease burden. Additionally, patients who were previously ineligible for radioimmunotherapy because of a greater than 25% bone-marrow involvement might be rendered eligible after initial chemotherapy, and the haematological toxic effects of radioimmunotherapy might be lessened because the marrow targeting is decreased. There are several published reports on radioimmunotherapy following chemotherapy and also following chemotherapy in combination with rituximab. The common theme in these phase II datasets is the ability of radioimmunotherapy to improve the quality of remission obtained after chemotherapy by converting partial responders to complete responders, consolidating complete response, or inducing a molecular remission. The expectation is that these improved responses will translate into lengthened disease-free intervals. The dataset with the longest follow-up in which such an approach was used is from the Southwest Oncology Group (SWOG) S9911 study.10 In this protocol, 90 untreated patients received six cycles of conventional CHOP chemotherapy followed by 131I-tositumomab. Responses were noted in 82 patients, 35 of whom had a complete response after chemotherapy and 62 of whom had a complete response after 131I–tositumomab. These responses seemed to be durable with a 5-year progression-free survival of 67% and with minimum long-term toxic effects. In another study, an alternative approach involved an abbreviated course (three cycles) of single-agent fludarabine, followed by 131I–tositumomab.11 Although chemotherapyinduced complete responses were less frequent (3 of 35 patients) with this regimen compared with that used in the SWOG study, the duration of treatment and toxic effects was decreased. However, after administration of 131I-tositumomab, the number of complete responders increased to 30 patients. http://oncology.thelancet.com Vol 9 April 2008
Reflection and Reaction
The findings from the FLUMIZ study support these data. The study population had a clear indication for treatment, and had a high initial response to fludarabine (43 of 61 patients had a complete response after chemotherapy). Only one patient did not respond and only three patiens had insufficient clearance of the bone marrow to preclude the 90Y-ibritumomab-tiuxetan phase. Sequential radioimmunotherapy improved most partial responses to complete responses with a remarkably high percentage of the per-protocol population (90%) achieving a complete response at the end of sequential treatment. In many cases, radioimmunotherapy induced molecular remissions where chemotherapy alone had failed to do so. These impressive responses seem to be durable (although follow-up is limited at a median of 30 months), and were achieved with an acceptable toxicity profile. The data from this study support the recently reported preliminary data from the phase III First-Line Indolent Trial (FIT) study,12 which assessed response consolidation with 90Y-ibritumomab tiuxetan after firstline chemotherapy chosen by the local investigator. Once remission had been achieved after chemotherapy, a large number of patients (n=414) were randomly assigned to observation or adjunctive radioimmunotherapy. The number of complete responses in the experimental group increased from 51% (106 of 208 patients) after chemotherapy to 87% (181 of 208 patients) after consolidation treatment, and progression-free survival was extended by 2 years compared with the control group (3·1 years vs 1·1 years, respectively). Thus, consolidation of first response by radioimmunotherapy seems to be a promising approach for the treatment of follicular lymphoma. The effect these sequential strategies will have on overall survival is yet to be seen, although historical comparisons presented by the SWOG group suggest that the effect will be significant.10 Furthermore, consideration needs to be given to the practicality of delivering subsequent treatments at the time of disease recurrence, including the delivery of high-dose chemotherapy supported by haemopoetic progenitor cells. Should the optimum initial treatment for follicular lymphoma involve a chemotherapy regimen that contains an anthracyline or fludarabine? Should the monoclonal antibody be given in combination with chemotherapy, as maintenance or as a sequential http://oncology.thelancet.com Vol 9 April 2008
radioimmunoconjugate? As we search for a strategy that achieves high responses, long disease-free periods, and minimum toxic effects, patient recruitment into phase III trials that focus on these endpoints needs to be encouraged. A single therapeutic approach might not be appropriate for all risk strata of follicular lymphoma and different groups of patients might benefit more from one type of approach compared with another. Andrew Davies Cancer Research UK Clinical Centre, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK [email protected] The author declared no conflicts of interest. 1
2
3
4
5
6
7
8 9
10
11
12
Friedberg JW, Huang J, Dillon H, et al. Initial therapeutic strategy in follicular lymphoma(FL): an analysis from the National LymphoCare Study (NLCS). Proc Am Soc Clin Oncol 2006; 24: (abstr 7527). Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–23. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–32. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25: 1986–92. Salles GA, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. Blood 2007; 110: (abstr 792). Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2002; 15: 2453–63. Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 2005; 23: 7565–73. Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352: 441–49. Zinzani PL, Tani M, Pulsoni A, et al. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol 2008; 9: 352–58. Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006; 24: 4143–49. Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005; 23: 5696–704. Hagenbeek A, Bischof-Delaloye A, Radford JA, et al. 90Y-ibritumomab tiuxetan (Zevalin(R)) consolidation of first remission in advanced stage follicular non-Hodgkin’s lymphoma: first results of the international randomized phase 3 First-Line Indolent Trial (FIT) in 414 patients. Blood 2007; 110: (abstr 643).
311
been shown to downregulate VEGF, decrease the amount of hypoxia in the prostate, and normalise vasculature.10 Vergis and colleagues have defined an appropriate population in which antihypoxic treatments should be studied. Bevacizumab, a VEGF sequestrant, has been assessed in patients with hormone-resistant prostate cancer and has shown encouraging findings in phase II trials. However, VEGF expression is only one aspect of hypoxia and a host of new anti-HIF-1-alpha drugs are in development. An appropriate setting for testing might be to administer drugs in the presurgical neoadjuvant setting and monitor their effect on hypoxic markers in prostatectomy specimens. The targeting of hypoxic cells has fallen out of favour in the past decade. Perhaps with the combination of effective biological interventions and appropriate patient stratification based upon Vergis’s data, antihypoxia drugs will once again enter the limelight. Yaacov Richard Lawrence, Adam P Dicker* Department of Radiation Oncology, Division of Experimental Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA [email protected]
The authors declared no conflicts of interest. YRL is supported by a grant from the “American Physicians’ Fellowship for Medicine in Israel”. 1 2
3 4
5
6
7
8
9
10
Alper T, Howard-Flanders P. Role of oxygen in modifying the radiosensitivity of E. coli B. Nature 1956; 178: 978–79. Bindra RS, Schaffer PJ, Meng A, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004; 24: 8504–18. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007; 26: 225–39. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447–54. Movsas B, Chapman JD, Greenberg RE, et al. Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2) study. Cancer 2000; 89: 2018–24. Movsas B, Chapman JD, Hanlon AL, et al. Hypoxic prostate/muscle pO2 ratio predicts for biochemical failure in patients with prostate cancer: preliminary findings. Urology 2002; 60: 634–39. Vergis R, Corbishley CM, Norman AR, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 2008; 9: 342–51. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60: 1541–45. Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601. Woodward WA, Wachsberger P, Burd R, Dicker AP. Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade. Prostate Cancer Prostatic Dis 2005; 8: 127–32.
Optimising initial treatment for follicular lymphoma The management of follicular lymphoma is not straightforward. Despite therapeutic advances and an improved understanding of disease biology, most efforts have resulted in promising, but only modest, improvements in overall survival. The frequently cited long clinical course misrepresents the difficulty of a relapsing disease, a continuous risk of transformation to more aggressive histologies, and extremes of survival where most patients will die either as a direct result of the disease or as a complication of treatment. The efficacy of external-beam radiotherapy in follicular lymphoma has been recognised for many decades, and, for the small number of patients who present with earlystage disease, durable remissions, and in some cases cures, can be achieved with this treatment modality. Most patients will, however, present at an advanced stage, and, for those who are asymptomatic or not compromised by the disease, there is a large amount of evidence of no improvement in survival after early http://oncology.thelancet.com Vol 9 April 2008
intervention with cytotoxic treatment; the best course of action for these patients is to reserve the use of such treatment for later in the disease course. However, such a policy of watchful waiting is nihilistic and is rightly being rechallenged in the era of rituximab, a monoclonal antibody directed against the CD20 antigen expressed on most malignant B cells. For patients who present with advanced-stage disease and who are in need of immediate treatment, because of symptoms or organ compromise, the choices for firstline treatment are broad, and, as evidenced by the US National Lymphocare study,1 there is clear diversity in the treatments used in clinical practice. In this setting, four randomised studies have shown that the addition of rituximab to conventional first-line chemotherapy regimens not only increases the overall number of responses, complete responses, and the duration of response, but also affects overall survival.2–5 Findings for the experimental groups in each of these phase III studies
See Articles page 352
309
John Cole/Science Photo Library
Reflection and Reaction
Patient receiving mitoxantrone, which can be augmented with radioimmunoconjugates
are impressive, with responses noted in 81–96% of patients, of which 20–75% had a complete response. The current diversity in clinical practice, therefore, does not arise from the inclusion of rituximab in initial treatment, but from the choice of which cytotoxic drugs should be used in combination with rituximab to achieve the best chance of a good-quality durable remission with acceptable toxic effects. In the USA, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is currently the regimen of choice.1 The radioimmunoconjugates iodine-131 (131I)-tositumomab and yttrium-90 (90Y)-ibritumomab tiuxetan consist of CD20-targeted monoclonal antibodies conjugated to a radionuclide. Therefore, these radiolabelled drugs harness the sensitivity of follicular lymphoma to both immunotherapy and radiotherapy, and both have shown significant activity in relapsed disease.6,7 In untreated patients, provocative data on the single-agent activity of 131I-tositumomab have been reported, showing responses in 95% (72 of 76 patients) of patients.8 131I-tositumomab can be administered over a single week and is free of many of the conventional non-haematological toxic effects of chemotherapy.8 However, the patients included in this study were a select group from the population of patients with follicular lymphoma because, not least, those with more than 25% bone-marrow infiltration were excluded due to the risk of increased myelotoxic effects. In this issue of The Lancet Oncology, Zinzani and co-workers9 report the findings of the FLUMIZ 310
(FLUdarabine, MItoxantrone, Zevalin) phase II multicentre trial, in which 57 patients with previously untreated follicular lymphoma received six cycles of fludarabine and mitoxantrone followed by 90Y-ibritumomab tiuxetan after documentation of a chemotherapy-induced response. The use of such a multimodal approach is an attractive option, because initial tumour debulking with chemotherapy can result in an optimum environment for successful radioimmunotherapy as a result of the low disease burden. Additionally, patients who were previously ineligible for radioimmunotherapy because of a greater than 25% bone-marrow involvement might be rendered eligible after initial chemotherapy, and the haematological toxic effects of radioimmunotherapy might be lessened because the marrow targeting is decreased. There are several published reports on radioimmunotherapy following chemotherapy and also following chemotherapy in combination with rituximab. The common theme in these phase II datasets is the ability of radioimmunotherapy to improve the quality of remission obtained after chemotherapy by converting partial responders to complete responders, consolidating complete response, or inducing a molecular remission. The expectation is that these improved responses will translate into lengthened disease-free intervals. The dataset with the longest follow-up in which such an approach was used is from the Southwest Oncology Group (SWOG) S9911 study.10 In this protocol, 90 untreated patients received six cycles of conventional CHOP chemotherapy followed by 131I-tositumomab. Responses were noted in 82 patients, 35 of whom had a complete response after chemotherapy and 62 of whom had a complete response after 131I–tositumomab. These responses seemed to be durable with a 5-year progression-free survival of 67% and with minimum long-term toxic effects. In another study, an alternative approach involved an abbreviated course (three cycles) of single-agent fludarabine, followed by 131I–tositumomab.11 Although chemotherapyinduced complete responses were less frequent (3 of 35 patients) with this regimen compared with that used in the SWOG study, the duration of treatment and toxic effects was decreased. However, after administration of 131I-tositumomab, the number of complete responders increased to 30 patients. http://oncology.thelancet.com Vol 9 April 2008
Reflection and Reaction
The findings from the FLUMIZ study support these data. The study population had a clear indication for treatment, and had a high initial response to fludarabine (43 of 61 patients had a complete response after chemotherapy). Only one patient did not respond and only three patiens had insufficient clearance of the bone marrow to preclude the 90Y-ibritumomab-tiuxetan phase. Sequential radioimmunotherapy improved most partial responses to complete responses with a remarkably high percentage of the per-protocol population (90%) achieving a complete response at the end of sequential treatment. In many cases, radioimmunotherapy induced molecular remissions where chemotherapy alone had failed to do so. These impressive responses seem to be durable (although follow-up is limited at a median of 30 months), and were achieved with an acceptable toxicity profile. The data from this study support the recently reported preliminary data from the phase III First-Line Indolent Trial (FIT) study,12 which assessed response consolidation with 90Y-ibritumomab tiuxetan after firstline chemotherapy chosen by the local investigator. Once remission had been achieved after chemotherapy, a large number of patients (n=414) were randomly assigned to observation or adjunctive radioimmunotherapy. The number of complete responses in the experimental group increased from 51% (106 of 208 patients) after chemotherapy to 87% (181 of 208 patients) after consolidation treatment, and progression-free survival was extended by 2 years compared with the control group (3·1 years vs 1·1 years, respectively). Thus, consolidation of first response by radioimmunotherapy seems to be a promising approach for the treatment of follicular lymphoma. The effect these sequential strategies will have on overall survival is yet to be seen, although historical comparisons presented by the SWOG group suggest that the effect will be significant.10 Furthermore, consideration needs to be given to the practicality of delivering subsequent treatments at the time of disease recurrence, including the delivery of high-dose chemotherapy supported by haemopoetic progenitor cells. Should the optimum initial treatment for follicular lymphoma involve a chemotherapy regimen that contains an anthracyline or fludarabine? Should the monoclonal antibody be given in combination with chemotherapy, as maintenance or as a sequential http://oncology.thelancet.com Vol 9 April 2008
radioimmunoconjugate? As we search for a strategy that achieves high responses, long disease-free periods, and minimum toxic effects, patient recruitment into phase III trials that focus on these endpoints needs to be encouraged. A single therapeutic approach might not be appropriate for all risk strata of follicular lymphoma and different groups of patients might benefit more from one type of approach compared with another. Andrew Davies Cancer Research UK Clinical Centre, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK [email protected] The author declared no conflicts of interest. 1
2
3
4
5
6
7
8 9
10
11
12
Friedberg JW, Huang J, Dillon H, et al. Initial therapeutic strategy in follicular lymphoma(FL): an analysis from the National LymphoCare Study (NLCS). Proc Am Soc Clin Oncol 2006; 24: (abstr 7527). Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–23. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–32. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25: 1986–92. Salles GA, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. Blood 2007; 110: (abstr 792). Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2002; 15: 2453–63. Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 2005; 23: 7565–73. Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352: 441–49. Zinzani PL, Tani M, Pulsoni A, et al. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol 2008; 9: 352–58. Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006; 24: 4143–49. Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol 2005; 23: 5696–704. Hagenbeek A, Bischof-Delaloye A, Radford JA, et al. 90Y-ibritumomab tiuxetan (Zevalin(R)) consolidation of first remission in advanced stage follicular non-Hodgkin’s lymphoma: first results of the international randomized phase 3 First-Line Indolent Trial (FIT) in 414 patients. Blood 2007; 110: (abstr 643).
311