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Infectious complications of monoclonal antibodies used in cancer therapy
A systematic review of the evidence from randomized controlled trials
Version of Record online: 11 APR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 11, pages 2182–2189, 1 June 2007
How to Cite
Rafailidis, P. I., Kakisi, O. K., Vardakas, K. and Falagas, M. E. (2007), Infectious complications of monoclonal antibodies used in cancer therapy. Cancer, 109: 2182–2189. doi: 10.1002/cncr.22666
- Issue online: 18 MAY 2007
- Version of Record online: 11 APR 2007
- Manuscript Accepted: 5 FEB 2007
- Manuscript Revised: 12 JAN 2007
- Manuscript Received: 13 NOV 2006
- infectious complications;
- monoclonal antibodies;
- randomized controlled trials;
- cancer treatment
The introduction of monoclonal antibodies (MoAbs) into the treatment of cancer has led to improvements in patient survival. However, to the authors' knowledge, little attention has been paid to the infectious complications associated with their use. The authors performed a systematic review of the literature to identify randomized controlled trials (RCTs) that included in their outcomes a comparison of the infectious complications of a MoAb plus chemotherapy or radiotherapy versus the therapy regimen given without the addition of a MoAb. Twenty RCTs with relevant data regarding the use of MoAbs in patients with hematologic malignancies (10 RCTs) and solid tumors (10 RCTs) were retrieved. Six RCTs compared rituximab in conjunction with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus CHOP alone for the treatment of B-cell non-Hodgkin lymphoma (NHL). No significant increase in the incidence of infections was observed with the addition of rituximab to chemotherapy (based on data from 5 RCTs). However, in patients who were seropositive for the human immunodeficiency virus (HIV), a 12% increase in infection-related deaths and a rate of higher opportunistic infections was associated with the rituximab-containing regimen (data taken from 1 RCT). Five RCTs either compared trastuzumab plus chemotherapy versus chemotherapy alone or trastuzumab monotherapy versus observation in patients with breast cancer. The addition of trastuzumab to the various chemotherapy regimens was found to cause a slight increase in the frequency of high-grade infections while bevacizumab caused a negligible increase in Grade III/IV infections compared with the same regimens given of chemotherapy alone. Based on a single trial, a higher comparable increase in the rate of high-grade infections was noted with the use of cetuximab in addition to chemotherapy compared with chemotherapy alone. MoAbs added to chemotherapy appear to have infectious complications that are comparable to the chemotherapy-alone regimen when administered for the treatment of NHL, with the exception of HIV-seropositive patients. Trastuzumab, which is reported to have a clear benefit in the prognosis of breast cancer patients, was found to cause a small increase in Grade III/IV infectious complications; however, there was no apparent difference in the rate of infection-related death. Cancer 2007. © 2007 American Cancer Society.
Systemic therapy is an integral part of the multidisciplinary curative treatment of various forms of cancers. Recent breakthroughs in research have established monoclonal antibodies (MoAbs) as effective and safe in the therapeutic battle against various malignancies such as non-Hodgkin lymphoma (NHL); chronic lymphocytic leukemia; acute myeloid leukemia; and breast, lung, renal cell, and colorectal cancer.1
MoAbs approved for treatment in cancer are either humanized (alemtuzumab and trastuzumab) or chimeric (bevacizumab, cetuximab, and rituximab). Despite having a common isotype, namely immunoglobulin (Ig) G1, they have different targets and induce cancer cell cytotoxicity in different ways. Alemtuzumab or anti-CD52 targets a specific surface marker on B cells and T cells, promoting their destruction. Therefore, it can act as a powerful antileukemic agent but also leads to profound and prolonged immunosuppression, giving rise to various opportunistic and nonopportunistic infections, as it depletes the body of B cells and T cells.2 Bevacizumab targets the vascular endothelial growth factor and cetuximab binds to the epidermal growth factor receptor. Rituximab targets the CD20 antigen and causes lysis of B-cell lines of NHL through complement and antibody-dependent cytotoxicity. A proportion of normal CD20 B cells are lyzed as well.3
Each MoAb is used either as monotherapy or, more commonly, is combined with other treatments, usually chemotherapy. Many randomized trials have focused on the testing of MoAb immunotoxins, bispecific constructs, and radioimmunoconjugates to demonstrate a survival benefit in cancer patients. However, to our knowledge, there is insufficient literature concerning the various adverse effects associated with the administration of MoAbs, including infectious complications. Therefore, the objective of the current review is to present the evidence from randomized controlled trials (RCTs) regarding the possible infectious complications of MoAbs used in the treatment of cancer.
MATERIALS AND METHODS
We searched the PubMed database (articles published through August 2006) for relevant RCTs. Search terms included “monoclonal antibodies,” “infections,” “infectious complications,” “rituximab,” “alemtuzumab,” “bevacizumab,” “trastuzumab,” and “cetuximab,” as well as combinations of these terms. In addition, references from the full articles that were reviewed were examined further for relevance.
Two reviewers (O.K. and K.V.) independently searched the literature to identify relevant studies for further inclusion in this review. A study was considered eligible if it was a RCT and compared data regarding infectious complications of a treatment regimen containing a Food and Drug Administration (FDA)-approved MoAb administered either as monotherapy or in combination with chemotherapy or radiation therapy versus a similar regimen given without the MoAb. RCTs including patients with either hematologic or solid malignancies were examined.
Only studies written in English or German were reviewed further and analyzed. In vitro studies and animal studies, case reports, case series, retrospective studies, prospective studies with an historical cohort as a control arm, and ongoing trials were excluded from this review. Studies in which both treatment arms contained MoAbs were excluded. Studies with radioimmunoconjugates also were excluded because the radioisotope component may confound any adverse effects attributable to the MoAb.4
Two reviewers (O.K. and P.I.R.) independently extracted data from the reviewed studies. Any disagreement between these reviewers was resolved by consensus in meetings with another author (M.E.F.). The following data were extracted from each study: patient population, treatment regimen received, number of patients receiving each regimen, infection rate, and types of infectious complications that arose.
In Figure 1, we present the study selection process used in the current review. From the initially retrieved 73 relevant articles, 27 RCTs were excluded in which both treatment arms contained MoAbs or in which the MoAb was a radioimmunoconjugate. From the remaining studies, 46 RCTs were found to meet the inclusion criteria. Of these 46 RCTs, 25 did not provide information regarding infectious complications and were not analyzed further. The remaining 21 RCTs (11 regarding hematologic malignancies and 10 regarding solid tumors) are presented in Tables 1 and 2, respectively.
|Reference||Study type||Type of cancer||Treatment||No. of patients||Infection rate||Type of infectious complication|
|Regimen 1||Regimen 2||Regimen 1||Regimen2||Regimen 1||Regimen 2||Regimen 1||Regimen 2|
|Pfreundshuh et al., 20065||RCT||NHL B-cell||Rituximab + CHOP||CHOP||413||411||7%||8%||Septicemia (0.5%)||Septicemia (0.25%)|
|Sepsis (0.25%) (Fischer test) P = .123 infection incidence in the 2 treatments.*|
|Habermann et al., 20066†||RCT||DLBCL||Rituximab + CHOP||CHOP||318||314||17%||16%||NSD||NSD|
|Feugier et al., 20057*– Coiffier et al. 20028*||RCT||DLBCL||Rituximab + CHOP||CHOP||202||197||Any grade 65%||Any grade 65%||Infection-related death (1.5%)||Infection related-death (0.5%)|
|Grade III/IV 12%||Grade III/IV 20%|
|Hiddemman et al., 20059||RCT Phase II||NHL follicular||Rituximab + CHOP||CHOP||223||205||5% including FUO||7% including FUO||Infection Grade I/II/III/IV: 15%/14%/6%/1% 4 infection-related deaths (1.7% of patients)||Infection Grade I/II/III/IV: 17%/16%/5%/0% 4 infection related deaths (1.9% of patients)|
|Lenz et al., 200510||RCT||NHL Mantle cell||Rituximab + CHOP||CHOP||62||60||Grade I/II 33%||Grade I/II 29%||NSD||NSD|
|Grade III/IV 5%||Grade III/IV 6%|
|Kaplan et al., 200511||RCT||NHL (In HIV- positive patients)||Rituximab + CHOP||CHOP||99||51||ND||ND||14% infection-related death||2% infection-related death (P = .035)|
|Gram-negative sepsis, 5%; gram-positive sepsis, 3%; sepsis-negative cultures, 6%; pneumonia-unspecified, 0.99%; fungal pneumonia, 0.99%||ND|
|Candida albicans fungemia (1) pneumonocystis pneumonia (3) esophageal candidiasis (1) CMV (2) and Mycobacterium avium (1)||No opportunistic infections|
|Forstpointer et al., 200412||RCT||NHL follicular and mantle cell||Rituximab + FCM||FCM||62||66||Grade III/IV 1.5%||Grade III/IV 1.5%||NSD||NSD|
|Marcus et al., 200413||RCT||NHL follicular||Rituximab + CVP||CVP||162||159||NSD||NSD||Infection||Infection|
|No difference between the 2 groups||Neutropenic sepsis||Neutropenic sepsis|
|Herold et al., 200314||RCT Phase III interim||Indolent NHL||Rituximab + MCP||MCP||55||51||NSD||NSD||NSD||NSD|
|No difference between the 2 groups (P = .41)|
|Wendtner et al., 200415||RCT||CLL in first remission||Alemtuzumab||Observation||11||10||90%||20%||Tuberculosis reactivation 1 (9%)||Herpes zoster 1 (10%)|
|Aspergillosis 1 (9%)||Sinusitis 1 (10%)|
|CMV reactivation 4 (36%)|
|Herpes zoster 1 (9%)|
|Bronchitis 1 (9%)|
|Gastroenteritis 1 (9%)|
|Sinusitis 1 (9%)|
|Reference||Study type||Type of cancer infectious||Treatment||Sample size||Infection rate||Complications|
|Regimen 1||Regimen 2||Regimen 1||Regimen 2||Regimen 1||Regimen 2||Regimen 1||Regimen 2|
|Joensuu et al., 200616||RCT||Breast cancer||Trastuzumab + docetaxel||Docetaxel||54||447||43.1% Grade I/II||39.2% Grade I/II||Infection, nonneutropenic||Infection, nonneutropenic|
|Infection, nonneutropenic||Infection, nonneutropenic|
|5.9% Grade III/IV||5.0% Grade III/IV||Febrile neutropenia 29.6%*||Febrile neutropenia 23%*|
|Trastuzumab + vinorelbine||Vinorelbine||61||446||32.8% Grade I/II||30% Grade I/II||Infection, nonneutropenic||Infection, nonneutropenic|
|Infection, nonneutropenic||Infection, nonneutropenic|
|1.6% Grade III/IV||2% Grade III/IV||Febrile neutropenia 4.9%*||Febrile neutropenia±|
|Marty et al., 200517||RCT||Breast cancer||Trastuzumab + docetaxel||Docetaxel||94||94||23%||17%||Febrile neutropenia||Febrile neutropenia|
|2% septic death|
|Slamon et al., 200118||RCT||Breast cancer||Trastuzumab+ chemotherapy (either antracycline + cyclophosphamide or paclitaxel)||Chemotherapy (either antracycline + cyclophosphamide or paclitaxel)||235||234||47%||29%||NSD||NSD|
|1 septic death|
|1 death secondary to hepatitis B related hepatorenal syndrome|
|Buzdar et al., 200519||RCT||Breast cancer||Trastuzumab + paclitaxel +5- fluorouracil + epirubicin + cyclophosphamide||Paclitaxel + 5-fluorouracil + epirubicin + cyclophosphamide||23||19||52%||36.8||Infection, nonneutropenic||Infection, nonneutropenic|
|Infection, neutropenic 21.7%||Infection, neutropenic 15.8%|
|Piccart-Gebhart et al., 200520||RCT||Breast cancer||Trastuzumab (1 or 2 years)||Observation||1677||1710||1.3% Grade III/IV 1.7% total||0.4% Grade III/IV 0.6% total||NSD||NSD|
|Miller et al., 200521||RCT||Metastatic breast cancer||Bevacizumab + capecitabine||Capecitabine||229||215||12.7% Grade II/III/IV||11.7% Grade II/III/IV||NSD||NSD|
|Johnson et al., 200422||RCT||Lung cancer||Bevacizumab (either low-dose or high-dose) +carboplatin + paclitaxel||Carboplatin + paclitaxel||32 (low dose)||32||31% (low dose)||25%||NSD||NSD|
|35 (high dose)||35% (high dose)|
|Kabbinavar et al., 200323||RCT||Metastatic colorectal cancer||Bevacizumab + 5- fluouracil + leucovorin||5-fluouracil + leucovorin||32 (low dose)||35||40%/0% (low dose)||20%/0%||NSD||NSD|
|Phase II||35 (high dose)||All events/ Grade III/IV||All events/ Grade III/IV|
|25%/1% (high dose)|
|Bonner et al., 200624||RCT||Squamous cell cancer of head and neck||Cetuximab + radiotherapy||Radiotherapy||211||213||6.6%||4.7%||NSD||NSD|
|Burtness et al., 200525||RCT||Head and neck cancer||Cetuximab plus cisplatin||Cisplatin||57||60||15% Grade III||10% Grade III||NSD||NSD|
With regard to the hematologic neoplasias, 7 of 11 trials tested rituximab with the addition of the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus CHOP chemotherapy alone. Infection rates were comparable in 4 RCTs comparing rituximab with CHOP (RCHOP) versus CHOP alone. More analytically, Pfreundshuh et al. found no statistically significant difference (P = .123) between the incidence of infection in either of the 2 treatment arms in their trial.5 In the study by Habermann et al., a 1% increase in the infection rate was observed in the RCHOP treatment arm versus the CHOP alone arm.6 In the study by Feugier et al., an approximately 1% increase in the rate of infection-related deaths was reported in patients receiving RCHOP compared with those receiving CHOP alone.7 Although there were no data regarding infection-related deaths in the study by Coiffier et al. in which RCHOP was compared with CHOP alone, there was a lower rate of infection (Grade III/IV) associated with the RCHOP regimen.8 In the RCT by Hiddemann et al., the overall infectious diseases profile was comparable because there was a 2% increased infection rate in the chemotherapy-alone regimen, but 2% more World Health Organization Grade III/IV infections occurred in the regimen containing MoAbs.9 In addition, the number of infection-related deaths were found to be similar in the 2 treatment arms (1.7% vs 1.9%). Similar data regarding the infection rates were extracted from the study by Lenz et al.10 Therefore, in 5 studies comparing RCHOP versus CHOP alone in patients who were not seropositive for the human immunodeficiency virus (HIV), the rate of infection was comparable in 3 studies and smaller in 1 study whereas a 1% increase in infection-associated mortality was found in 1 study.
In contrast, in the what to our knowledge was the only study with data from an HIV- seropositive population with lymphoma treated with RCHOP versus CHOP, there was a statistically significant difference in the infection-related death rate (14% vs 2%; P = .035). It is interesting to note that opportunistic infections were reported only in the RCHOP treatment arm.11
In addition to the above-mentioned RCTs, rituximab was administered with other, non-CHOP-containing chemotherapeutic agents as well for the treatment of hematologic malignancies. Three RCTs revealed no statistically significant difference with regard to the infection rate when comparing the RCHOP regimen versus the chemotherapy alone regimen.12–14 A study with a small number of patients by Wendtner et al. showed a 70% increase in total infectious complications in patients receiving alemtuzumab versus those patients in the observation arm.15
With regard to the treatment of solid tumors, 5 of 10 RCTs included in the current review reported data concerning therapy regimens containing trastuzumab for the treatment of patients with breast cancer. Two of these studies compared trastuzumab plus docetaxel versus docetaxel alone, 2 compared trastuzumab in addition to an anthracycline-based regimen versus chemotherapy alone, and 1 study compared trastuzumab versus observation. Specifically, Joensuu et al. found a difference of 3.9% in the rate of Grade I/II infections and 0.9% in the rate of Grades III/IV infection, with more infections occurring in the trastuzumab plus docetaxel regimen than in the doxecatel alone treatment arm.16 The same study showed a 2.8% greater rate of Grade I/II infection but a 0.4% smaller rate of Grade III/IV infection in those patients treated with trastuzumab plus vinorelbine versus patients treated with vinorelbine alone.16 Marty et al. similarly showed a 6% higher rate of infection in the trastuzumab plus docetaxel combination compared with the docetaxel alone regimen. It is interesting to note however that the infection-related death rate (2%) was higher in the docetaxel alone treatment arm.17 Slamon et al. reported that trastuzumab in addition to an antracycline-based chemotherapeutic regimen resulted in 18% more infections than the chemotherapeutic regimen alone.18 Buzdar et al. showed that trastuzumab in combination with chemotherapy (paclitaxel, 5-fluouracil, epirubicin, and cyclophosphamide) caused 15.2% more infections than chemotherapy alone, but it should be noted that their sample size was relatively small (23 patients vs 19 patients).19 In a large RCT with a total of 3387 patients conducted by Piccart-Gebhart et al., infection-related events associated with the trastuzumab regimen exceeded those of the observation arm by 0.9% and 1.1%, respectively, for Grade III/IV infections and total infections.20
Bevacizumab combined with capecitabine was associated with 1% more infections than capecitabine alone in the RCT by Miller et al.21 Similarly, when bevacizumab (in both low and high doses) was combined with carboplatin and paclitaxel, it was found to augment the incidence of infections by 6% to 10% compared with the chemotherapy alone regimen.22 Kabbinavar et al. showed a 5% and 20% increase, respectively, in infections in the high-dose and low-dose bevacizumab treatment arms compared with the chemotherapy alone arms.23 In the RCT by Bonner et al., the infection rate was increased by 1.9% in the cetuximab plus radiotherapy arm compared with the radiotherapy alone arm in the treatment of squamous cell carcinomas of the head and neck.24 Burtness et al. showed a 5% increase in Grade III infections in the cetuximab plus cisplatin arm compared with the cisplatin alone arm.25
MoAbs have arisen from the emergence of recombinant technologies in biomedical production and have proved themselves useful in the treatment of malignancies. The immunogenicity associated with murine MoAbs has decreased substantially with the introduction of chimeric and humanized antibodies. Immunogenicity resulting from hypersensitivity to xenogeneic sequences rarely can manifest as anaphylactic shock or, more commonly, as an infusion-related syndrome with fever, chills, nausea, or rigors, or cause tumor lysis or thrombocytopenia.3
Other adverse reactions, especially infections, occur as a direct consequence of the mechanistic action of MoAbs. For example, an increase in the incidence of tuberculosis is noted with the use of anti-tumor necrosis factor-α for the treatment of rheumatoid arthritis. In cancer therapeutics, the use of rituximab leads to the destruction of malignant CD20-bearing lymphocytes. Because a proportion of normal CD20-bearing lymphocytes are inevitably depleted as well, lymphopenia ensues and infections may emerge. CD52-targeting therapy will similarly target both malignant lymphocytes as well as a proportion of normal lymphocytes and lead to lymphopenia. The use of alemtuzumab has been reported in association with cases of oral candidiasis, Listeria monocytogenes bacteraemia, and meningitis; disseminated varicella-zoster virus infections; the reactivation of cytomegalovirus and herpes simplex virus; various forms of pneumonia; and septicemia.2
In our review, we sought to gather the evidence from RCTs to clarify whether the use of MoAbs in the treatment of hematologic malignancies and solid tumors is indeed associated with an increased risk of infection. The majority of data from RCTs regarding hematologic malignancies pertain to the use of rituximab in patients with NHL. Based on the data extracted from the reviewed RCTs, the addition of rituximab to CHOP in the treatment of NHL in patients without HIV seropositivity does not appear to influence the incidence of infectious complications significantly. Only 3 RCTs reported on the use of rituximab plus a regimen other than CHOP versus the same regimen alone, and these reports demonstrated comparable data regarding the infectious profile of the 2 treatment arms.12–14
In contrast, Kaplan et al. reported on an HIV-seropositive population with lymphoma that was treated with RCHOP versus CHOP, and found a statistically significant 12% increase in infection-related deaths in those patients treated on the rituximab-containing treatment arm. In addition, opportunistic infections were reported only in the rituximab-containing arm as well.11 The induction of lymphopenia in HIV-positive patients appears to have a significant effect on the rate of infection-related death in this subgroup of patients, who are already immunocompromised. One may speculate that the concomitant affliction of B-lymphocytes (due to the MoAb) and T-lymphocytes (due to the HIV infection) presents an overwhelming burden for the immune system. Therefore, increased surveillance most likely is needed when rituximab is administered to HIV-positive patients with NHL, especially if the CD4 count is <50/mm3.
Alemtuzumab is clearly a advancement in the treatment of chronic lymphoproliferative diseases and simultaneously is associated with an increased risk of infection.15 Prophylaxis against herpes simplex virus infection and Pneumocystis jiroveci pneumonia appears to be warranted in patients treated with alemtuzumab.2
From the 10 RCTs performed in patients with solid tumors that were eligible for our review, we identified 5 that examined the use of trastuzumab in patients with breast cancer. In the 2 studies by Joensuu et al.16 and Marty et al.17 that compared trastuzumab plus docetaxel versus docetaxel alone, increases of 4.8% and 6%, respectively, in the total number of Grade I-IV infections were observed in the trastuzumab treatment arms. Nevertheless, conclusions must be drawn with caution because only a 0.9% increase in Grade III/IV infections was noted in the study by Joensuu et al.,16 whereas the rate of septic death was comparably higher in the docetaxel alone treatment arm in the study by Marty et al.17 Conversely, Slamon et al. showed an 18% higher rate of infection and an increase in infection-related deaths in the trastuzumab only treatment arm.18 However, outcomes in this study were superior in terms of the lower overall rate of death at 1 year, yielding a 20% risk reduction with an increase in overall survival observed with the addition of trastuzumab to chemotherapy.18 A similar increase in infections (15.2%) was reported by Buzdar et al., but the small study sample in their report must be taken into account when interpreting the findings.19 Finally, in a large study comparing trastuzumab with observation alone, a 0.9% increase in Grade III/IV infections was noted in the patients receiving trastuzumab.20 Therefore, although there appears to be a small trend toward increased infections in the trastuzumab-containing regimen, it may be an acceptable price to pay given the high rate of disease-related mortality observed in breast cancer patients.
One RCT regarding the use of bevacizumab plus chemotherapy versus chemotherapy alone in lung cancer patients showed a 6% to 10% increase in the number of infections.22 Similarly, in a study of patients with metastatic colorectal cancer, a 5% to 20% increase in the rate of infection was reported in the bevacizumab-containing treatment arm.23 However, there was no increase observed in Grade III/IV infections in the low-dose bevacizumab treatment arm and a 1% increase was noted in the high-dose bevacizumab treatment arm. Therefore, it is difficult to draw firm conclusions regarding the infectious potential of bevacizumab from the use of antivascular endothelial growth factor in these different malignancies. Therefore, despite an increase in the number of total infections noted with the use of bevacizumab combined with chemotherapy, the incidence of severe infections may be comparable to those observed with chemotherapy given alone in the setting of lung and metastatic colorectal cancer.
Comparable infectious complications are noted in the treatment of patients with NHL when rituximab is added to a chemotherapy regimen compared with the administration of the chemotherapy regimen alone, with the exception of HIV-seropositive patients. Trastuzumab, which has a clear benefit in the treatment of breast cancer patients, causes a small increase in Grade III/IV infectious complications without an increase in the rate of infection-related death. Because it is possible that new classes of genetically optimized antibodies and MoAb fragments will enter into clinical practice, physicians need to be aware of their potential risk for increasing infectious complications among patients receiving cancer therapy.
- 5CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006; 7(5): 379–391., , , et al.
- 9Frontline 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: 3725–3732., , , et al.
- 10Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005; 23: 1984–1992., , , et al.
- 12The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004; 104: 3064–3071., , , et al.
- 15Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia(CLL) in first remission—experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004; 18: 1093–1101., , , et al.
- 17Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005; 23: 4265–4274., , , et al.
- 19Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005; 23: 3676–3685., , , et al.