Annals of Oncology reviews
untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin
J Clin Oncol 2014; 32: 2240–2247. Oncol 2014; 32: abstr LBA3.
17. Karthaus M, Schwartzberg L, Rivera F et al. Updated overall survival (OS) analysis 22. Tveit K, Guren T, Glimelius B et al. Phase III trial of cetuximab with continuous or
of novel predictive KRAS/NRAS mutations beyond KRAS exon 2 in PEAK: A 1st-line intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in
phase 2 study of FOLFOX6 plus panitumumab ( pmab) or bevacizumab (bev) in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J Clin Oncol
metastatic colorectal cancer (mCRC). Eur J Cancer 2013; 49: S516. 2012; 30: 1755–1762.
18. Ciardiello F, Lenz HJ, Kohne CH et al. Treatment outcome according to tumor RAS 23. Sobrero AF, Maurel J, Fehrenbacher L et al. EPIC: phase III trial of cetuximab plus
mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic
randomized to FOLFIRI with/without cetuximab. J Clin Oncol 2014; 32: abstr 3506. colorectal cancer. J Clin Oncol 2008; 26: 2311–2319.
19. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab 24. Jonker DJ, Karapetis C, Harbison CT. Epiregulin gene expression as a biomarker
efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: of benefit from cetuximab in the treatment of advanced colorectal cancer. Br J
1626–1634. Cancer 2014; 110: 648–655.
20. Jonker DJ, O’Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of 25. Sartore-Bianchi A, Martini M, Molinari F et al. PIK3CA mutations in colorectal
colorectal cancer. N Engl J Med 2007; 357: 2040–2048. cancer are associated with clinical resistance to EGFR-targeted antibodies. Cancer
21. Venook AP, Niedzwiecki D, Lenz HJ et al. CALGB/SWOG 80405: Phase III trial of Res 2009; 69: 1851–1857.
irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) 26. De Roock W, De Vriendt V, Normanno N et al. KRAS, BRAF, PIK3CA, and PTEN
with bevacizumab (BV) or cetuximab (CET) for patients ( pts) with KRAS wild-type mutations: implications for targeted therapies in metastatic colorectal cancer.
Lancet Oncol 2010; 12: 594–603.
Annals of Oncology 26: 21–33, 2015
doi:10.1093/annonc/mdu192
Published online 15 May 2014
Diagnosis and antimicrobial therapy of lung infiltrates in
febrile neutropenic patients (allogeneic SCT excluded):
updated guidelines of the Infectious Diseases Working
Party (AGIHO) of the German Society of Hematology and
Medical Oncology (DGHO)†
G. Maschmeyer1*, J. Carratalà2, D. Buchheidt3, A. Hamprecht4, C. P. Heussel5, C. Kahl6, J. Lorenz7,
S. Neumann8, C. Rieger9, M. Ruhnke10, H. Salwender11, M. Schmidt-Hieber12 & E. Azoulay13
1
Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany; 2Department of Infectious Diseases, Bellvitge University
Hospital, University of Barcelona, Barcelona, Spain; 3Department of Hematology and Oncology, Mannheim University Hospital, Mannheim; 4Institution for Medical
Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne; 5Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik,
University Hospital, Heidelberg; 6Department of Hematology and Oncology, Klinikum Magdeburg, Magdeburg; 7Department of Pneumology, Infectious Diseases, Sleep
Medicine and Intensive Care, Klinikum Lüdenscheid, Lüdenscheid; 8Medical Oncology, AMO MVZ, Wolfsburg; 9Department of Medicine III, University Hospital Großhadern,
München; 10Department of Medical Oncology and Hematology, Charité University Medicine Campus Mitte, Berlin; 11Department of Hematology, Oncology, Stem Cell
Transplantation, Asklepios Klinik Altona, Hamburg; 12Department of Hematology, Oncology and Tumor Immunology, Helios-Klinikum Berlin-Buch, Berlin, Germany;
13
AP-HP, Hopital Saint-Louis, Service de Réanimation Médicale, Université Paris-Diderot, Sorbonne Paris-Cité, Faculté de Médecine, Paris, France
Received 22 February 2014; revised 29 April 2014; accepted 2 May 2014
Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not
respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of
cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory
viruses may be involved. In at-risk patients who have received trimethoprim–sulfamethoxazole (TMP/SMX) prophylaxis,
filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation.
*Correspondence to: Prof. Georg Maschmeyer, Department of Hematology, Oncology
and Palliative Care, Klinikum Ernst von Bergmann, Charlottenstrasse 72, D-14467
Potsdam, Germany. Tel: +49-331-241-6002; Fax: +49-331-241-6000; E-mail:
†
This manuscript does not refer to patients undergoing allogeneic hematopoietic stem
cell transplantation. These patients are subject to a separate AGIHO guideline [1].
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
This is an Open Access article under the CC-BY-NC license.
, reviews Annals of Oncology
Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for
the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting
Aspergillus galactomannan, β-D-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however,
most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary
side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be
included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment
with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated
only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia,
while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable
number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unre-
strictedly provided in patients whose prognosis is not desperate due to other reasons.
Key words: diagnosis, fever, lung infiltrates, neutropenia, pneumonia, treatment
introduction consensus process including tuberculosis, sarcoidosis or cryptogenic organizing
pneumonia [12].
See supplementary Material, available at Annals of Oncology Beyond early identification of LI, CT findings may allow for
online (Table 7). distinguishing fungal from nonfungal LI [13–18]. Diffuse bilat-
eral perihilar infiltrates, patchy areas of ground-glass attenuation
( peripheral sparing), cysts and septal thickening, consolidation
clinical baseline and centrilobular nodules may indicate PcP [19–21]. Nodular or
See supplementary Material, available at Annals of Oncology cavitary lesions are suggestive of invasive filamentous fungal infec-
online. tion; however, differential diagnoses include pneumonia due to
other microorganisms including mycobacteria [22] (which may be
relevant in regions with high prevalence), Nocardia, Pneumocystis
diagnostic procedures or Pseudomonas aeruginosa (P. aeruginosa) as well as lung in-
With respect to the critical prognosis of lung infiltrates (LI) in volvement by underlying malignancies [23], so that comparison
febrile neutropenic patients, diagnostic procedures are of major to previous CT scans in an individual patient is essential.
importance, but should not cause a substantial delay in the start Combination of CT scan with angiography has been found to
of adequate antimicrobial therapy. increase the diagnostic specificity in some patients with pul-
monary mold infections [24, 25]; however, this more labor in-
tensive method has not yet become widely applied and is
imaging therefore not included into current clinical practice guidelines.
Conventional chest radiographs show abnormalities in <2% of In selected patients where pulmonary CT scan is not wanted or
febrile neutropenic patients without clinical findings indicating feasible, magnetic resonance tomography (MRI) is a valid alter-
lower respiratory tract infection [2–4]. It is undetermined how native (B-II) [26, 27]. As yet, consensus definitions of invasive
many of these patients would have abnormalities on computed fungal diseases [10] have not included thoracic MRI findings. In
tomography (CT) scans, because no randomized head-to-head selected patients with unexplained fever during neutropenia,
comparisons have been published so far. In patients persistently [18F]2-fluoro-2-deoxy-D-glucose–positron emission tomography
febrile after >48 h of broad-spectrum antibacterial therapy, combined with computed tomography (PET-CT) may be helpful,
∼10% of chest radiographs are abnormal, whereas high- particularly to rule out undetected infection [28].
resolution CT scans at this time reveal pathological findings in Follow-up thoracic CT scans should in general not be ordered
∼50% of patients [5, 6]. Early detection of lesions indicating in- <7 days after start of treatment (A-II). In patients with IPA may
vasive mold infection or Pneumocystis pneumonia (PcP) is of show increasing volume of pulmonary infiltrates during the first
utmost importance, facilitating targeted bronchoscopy and week despite effective antifungal therapy [29]. This finding alone
bronchoalveolar lavage (BAL) and a prompt institution of pre- should not give reason to assess the treatment course as refractory
emptive antimicrobial treatment [7–9], enabling better survival (A-II). Reduction of the ‘halo’ and the development of an ‘air-
of these patients. CT findings such as consolidation, ‘halo sign’ crescent’ sign, however, typically indicate favorable response [30].
and ‘air-crescent sign’, obtained by high-resolution or multislice
CT scans, may be important signs of filamentous fungal disease
[8, 10]. While the ‘halo sign’ has been described typically in neu- microbiology and histopathology
tropenic patients, other CT findings indicative of IPA are com- In the majority of febrile neutropenic patients with LI, no
parable in neutropenic and in non-neutropenic patients [11]. A proving microbiological finding is available, so that the thera-
‘reversed halo sign’, showing a focal rounded area of ground- peutic management is based upon clinical and imaging findings
glass opacity surrounded by a crescent or complete ring of con- (see below). In microbiologically documented cases, pathogens
solidation, has been reported as relatively specific for fungal typically are isolated from blood cultures, bronchial secretions
pneumonia due to zygomycetes/mucorales [8]; however, it may or BAL fluid. It often means a challenge to assess the diagnostic
represent a broad spectrum of other differential diagnoses relevance of culture results [31–34], because unselected
| Maschmeyer et al. Volume 26 | No. 1 | January 2015
untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin
J Clin Oncol 2014; 32: 2240–2247. Oncol 2014; 32: abstr LBA3.
17. Karthaus M, Schwartzberg L, Rivera F et al. Updated overall survival (OS) analysis 22. Tveit K, Guren T, Glimelius B et al. Phase III trial of cetuximab with continuous or
of novel predictive KRAS/NRAS mutations beyond KRAS exon 2 in PEAK: A 1st-line intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in
phase 2 study of FOLFOX6 plus panitumumab ( pmab) or bevacizumab (bev) in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J Clin Oncol
metastatic colorectal cancer (mCRC). Eur J Cancer 2013; 49: S516. 2012; 30: 1755–1762.
18. Ciardiello F, Lenz HJ, Kohne CH et al. Treatment outcome according to tumor RAS 23. Sobrero AF, Maurel J, Fehrenbacher L et al. EPIC: phase III trial of cetuximab plus
mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic
randomized to FOLFIRI with/without cetuximab. J Clin Oncol 2014; 32: abstr 3506. colorectal cancer. J Clin Oncol 2008; 26: 2311–2319.
19. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab 24. Jonker DJ, Karapetis C, Harbison CT. Epiregulin gene expression as a biomarker
efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: of benefit from cetuximab in the treatment of advanced colorectal cancer. Br J
1626–1634. Cancer 2014; 110: 648–655.
20. Jonker DJ, O’Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of 25. Sartore-Bianchi A, Martini M, Molinari F et al. PIK3CA mutations in colorectal
colorectal cancer. N Engl J Med 2007; 357: 2040–2048. cancer are associated with clinical resistance to EGFR-targeted antibodies. Cancer
21. Venook AP, Niedzwiecki D, Lenz HJ et al. CALGB/SWOG 80405: Phase III trial of Res 2009; 69: 1851–1857.
irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) 26. De Roock W, De Vriendt V, Normanno N et al. KRAS, BRAF, PIK3CA, and PTEN
with bevacizumab (BV) or cetuximab (CET) for patients ( pts) with KRAS wild-type mutations: implications for targeted therapies in metastatic colorectal cancer.
Lancet Oncol 2010; 12: 594–603.
Annals of Oncology 26: 21–33, 2015
doi:10.1093/annonc/mdu192
Published online 15 May 2014
Diagnosis and antimicrobial therapy of lung infiltrates in
febrile neutropenic patients (allogeneic SCT excluded):
updated guidelines of the Infectious Diseases Working
Party (AGIHO) of the German Society of Hematology and
Medical Oncology (DGHO)†
G. Maschmeyer1*, J. Carratalà2, D. Buchheidt3, A. Hamprecht4, C. P. Heussel5, C. Kahl6, J. Lorenz7,
S. Neumann8, C. Rieger9, M. Ruhnke10, H. Salwender11, M. Schmidt-Hieber12 & E. Azoulay13
1
Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany; 2Department of Infectious Diseases, Bellvitge University
Hospital, University of Barcelona, Barcelona, Spain; 3Department of Hematology and Oncology, Mannheim University Hospital, Mannheim; 4Institution for Medical
Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne; 5Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik,
University Hospital, Heidelberg; 6Department of Hematology and Oncology, Klinikum Magdeburg, Magdeburg; 7Department of Pneumology, Infectious Diseases, Sleep
Medicine and Intensive Care, Klinikum Lüdenscheid, Lüdenscheid; 8Medical Oncology, AMO MVZ, Wolfsburg; 9Department of Medicine III, University Hospital Großhadern,
München; 10Department of Medical Oncology and Hematology, Charité University Medicine Campus Mitte, Berlin; 11Department of Hematology, Oncology, Stem Cell
Transplantation, Asklepios Klinik Altona, Hamburg; 12Department of Hematology, Oncology and Tumor Immunology, Helios-Klinikum Berlin-Buch, Berlin, Germany;
13
AP-HP, Hopital Saint-Louis, Service de Réanimation Médicale, Université Paris-Diderot, Sorbonne Paris-Cité, Faculté de Médecine, Paris, France
Received 22 February 2014; revised 29 April 2014; accepted 2 May 2014
Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not
respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of
cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory
viruses may be involved. In at-risk patients who have received trimethoprim–sulfamethoxazole (TMP/SMX) prophylaxis,
filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation.
*Correspondence to: Prof. Georg Maschmeyer, Department of Hematology, Oncology
and Palliative Care, Klinikum Ernst von Bergmann, Charlottenstrasse 72, D-14467
Potsdam, Germany. Tel: +49-331-241-6002; Fax: +49-331-241-6000; E-mail:
†
This manuscript does not refer to patients undergoing allogeneic hematopoietic stem
cell transplantation. These patients are subject to a separate AGIHO guideline [1].
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
This is an Open Access article under the CC-BY-NC license.
, reviews Annals of Oncology
Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for
the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting
Aspergillus galactomannan, β-D-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however,
most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary
side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be
included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment
with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated
only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia,
while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable
number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unre-
strictedly provided in patients whose prognosis is not desperate due to other reasons.
Key words: diagnosis, fever, lung infiltrates, neutropenia, pneumonia, treatment
introduction consensus process including tuberculosis, sarcoidosis or cryptogenic organizing
pneumonia [12].
See supplementary Material, available at Annals of Oncology Beyond early identification of LI, CT findings may allow for
online (Table 7). distinguishing fungal from nonfungal LI [13–18]. Diffuse bilat-
eral perihilar infiltrates, patchy areas of ground-glass attenuation
( peripheral sparing), cysts and septal thickening, consolidation
clinical baseline and centrilobular nodules may indicate PcP [19–21]. Nodular or
See supplementary Material, available at Annals of Oncology cavitary lesions are suggestive of invasive filamentous fungal infec-
online. tion; however, differential diagnoses include pneumonia due to
other microorganisms including mycobacteria [22] (which may be
relevant in regions with high prevalence), Nocardia, Pneumocystis
diagnostic procedures or Pseudomonas aeruginosa (P. aeruginosa) as well as lung in-
With respect to the critical prognosis of lung infiltrates (LI) in volvement by underlying malignancies [23], so that comparison
febrile neutropenic patients, diagnostic procedures are of major to previous CT scans in an individual patient is essential.
importance, but should not cause a substantial delay in the start Combination of CT scan with angiography has been found to
of adequate antimicrobial therapy. increase the diagnostic specificity in some patients with pul-
monary mold infections [24, 25]; however, this more labor in-
tensive method has not yet become widely applied and is
imaging therefore not included into current clinical practice guidelines.
Conventional chest radiographs show abnormalities in <2% of In selected patients where pulmonary CT scan is not wanted or
febrile neutropenic patients without clinical findings indicating feasible, magnetic resonance tomography (MRI) is a valid alter-
lower respiratory tract infection [2–4]. It is undetermined how native (B-II) [26, 27]. As yet, consensus definitions of invasive
many of these patients would have abnormalities on computed fungal diseases [10] have not included thoracic MRI findings. In
tomography (CT) scans, because no randomized head-to-head selected patients with unexplained fever during neutropenia,
comparisons have been published so far. In patients persistently [18F]2-fluoro-2-deoxy-D-glucose–positron emission tomography
febrile after >48 h of broad-spectrum antibacterial therapy, combined with computed tomography (PET-CT) may be helpful,
∼10% of chest radiographs are abnormal, whereas high- particularly to rule out undetected infection [28].
resolution CT scans at this time reveal pathological findings in Follow-up thoracic CT scans should in general not be ordered
∼50% of patients [5, 6]. Early detection of lesions indicating in- <7 days after start of treatment (A-II). In patients with IPA may
vasive mold infection or Pneumocystis pneumonia (PcP) is of show increasing volume of pulmonary infiltrates during the first
utmost importance, facilitating targeted bronchoscopy and week despite effective antifungal therapy [29]. This finding alone
bronchoalveolar lavage (BAL) and a prompt institution of pre- should not give reason to assess the treatment course as refractory
emptive antimicrobial treatment [7–9], enabling better survival (A-II). Reduction of the ‘halo’ and the development of an ‘air-
of these patients. CT findings such as consolidation, ‘halo sign’ crescent’ sign, however, typically indicate favorable response [30].
and ‘air-crescent sign’, obtained by high-resolution or multislice
CT scans, may be important signs of filamentous fungal disease
[8, 10]. While the ‘halo sign’ has been described typically in neu- microbiology and histopathology
tropenic patients, other CT findings indicative of IPA are com- In the majority of febrile neutropenic patients with LI, no
parable in neutropenic and in non-neutropenic patients [11]. A proving microbiological finding is available, so that the thera-
‘reversed halo sign’, showing a focal rounded area of ground- peutic management is based upon clinical and imaging findings
glass opacity surrounded by a crescent or complete ring of con- (see below). In microbiologically documented cases, pathogens
solidation, has been reported as relatively specific for fungal typically are isolated from blood cultures, bronchial secretions
pneumonia due to zygomycetes/mucorales [8]; however, it may or BAL fluid. It often means a challenge to assess the diagnostic
represent a broad spectrum of other differential diagnoses relevance of culture results [31–34], because unselected
| Maschmeyer et al. Volume 26 | No. 1 | January 2015
