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collection of archival tumour material for study entry, which is becoming generalised for many phase 1–2 trials, particularly when this collection could clearly benefi t other patients in this or subsequent studies. Patients with neuroblastoma and unknown ALK status barely benefi ted from crizotinib in this study, and to understand the reasons behind the lack of clinical response is crucial. There is a need to identify the best predictive biomarker for ALK inhibition, and mutations, amplifi cation, and mRNA or protein overexpression are potential candidates.

Moreover, the study1 seemed to contain two diff erent groups of patients: those with ALK translocations (ALCL, IMT, and NSCLC) who overall had outstanding benefi ts from the single-agent crizotinib despite being heavily pretreated (12 of 18 experienced responses) and children with ALK-mutated neuroblastoma, for whom responses were not optimum for such targeted therapy (only one patient of 11 responsed). This result could be related to inherent primary resistance of ALK-mutant tumours or insuffi cient target inhibition, and here, pharmacodynamic biomarkers embedded in clinical trials might have provided further insights. This understanding is crucial for designing subsequent studies. For example, Berry and colleagues7 have suggested preclinically that the addition of mammalian target of rapamycin complex (mTORC) inhibitors can overcome resistance to crizotinib.

In conclusion, this is a well conducted phase 1 trial with good quality data, which achieved its primary goals successfully and will help subsequent phase 2 trials. It was completed in a realistic timeframe for such an infrequent population with the number of dose levels

and cohorts tested. This study constitutes a landmark in bringing molecularly targeted therapies into children and adolescents with poor-prognosis cancers. It is clear that the new era of clinical trials demand the incorporation of biomarkers testing biological hypotheses in paediatric early clinical trials to accelerate and improve the drug development process.

Lucas Moreno Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain, and Paediatric Drug Development, Children and Young People’s Unit, The Royal Marsden NHS Foundation Trust, Sutton, UKlmorenom@cnio.es

I declare that I have no confl icts of interest.

1 Mossé YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013; published online April 16. http://dx.doi.org/10.1016/S1470-2045(13)70095-0.

2 George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 2008; 455: 975–78.

3 Chen Y, Takita J, Choi YL, et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 2008; 455: 971–74.

4 Janoueix-Lerosey I, Lequin D, Brugières L, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 2008; 455: 967–70.

5 Mossé YP, Laudenslager M, Longo L, et al. Identifi cation of ALK as a major familial neuroblastoma predisposition gene. Nature 2008; 455: 930–35.

6 Matthay KK, George RE, Yu AL. Promising therapeutic targets in neuroblastoma. Clin Cancer Res 2012; 18: 2740–53.

7 Berry T, Luther W, Bhatnagar N, et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 2012; 22: 117–30.

8 Heukamp LC, Thor T, Schramm A, et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med 2012; 4: 141ra91.

9 Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363: 1693–703.

10 Kim A, Fox E, Warren K, et al. Characteristics and outcome of pediatric patients enrolled in phase I oncology trials. Oncologist 2008; 13: 679–89.

Published OnlineApril 15, 2013

http://dx.doi.org/10.1016/S1470-2045(13)70133-5

See Articles pages 481 and 490

Targeted therapy for gastric cancerThe epidermal growth factor receptor family consists of four members—EGFR (HER1), HER2, HER3, and HER4. Although HER2 alone is not able to bind to any of the known ligands, such as EGF, a heterodimer formation with EGFR, HER3, or HER4 creates a potent signal-transduction pathway. Activation of EGFR and HER2 expression in several types of tumour can lead to uncontrolled proliferation of tumour cells. Because EGFR and HER2 are overexpressed in a subset of oesophageal, gastric, and colorectal cancer, these receptors are strong candidates for targeted therapy. Cetuximab is a human-murine chimeric anti-EGFR monoclonal antibody and

panitumumab is a human monoclonal antibody specifi c to human EGFR. Trastuzumab, an anti-HER2 antibody, is eff ective for treatment of HER2-positive gastric and gastro-oesophageal junction cancer, with increased benefi ts reported in patients with high levels of HER2 expres sion.1 HER2 is overexpressed in 6–36% of gastric cancers, with increasingly proximal tumours more likely to overexpress HER2 compared with distal tumours.2 EGFR overexpression is reported in 9–27% of gastric cancers, also with more proximal tumours overexpressing EGFR than distal tumours.3,4 Phase 2 trials assessing the effi cacy of cetuximab combined with chemotherapy for

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advanced gastric cancer resulted in acceptable tumour response rates and drug toxicity. Relevant data for panitumumab are scarce, but much the same eff ects as for cetuximab would be expected.

Two randomised phase 3 trials are presented in The Lancet Oncology that assessed anti-EGFR antibodies for treatment of gastric cancer. The EXPAND trial5 recruited 904 patients with metastatic or locally advanced gastric cancer who were randomly assigned to receive chemotherapy (capecitabine plus cisplatin) or chemotherapy plus cetuximab. Disappointingly, addition of cetuximab to chemotherapy provided no benefi t in progression-free survival (PFS, the primary endpoint; 5·6 months [95% CI 5·1–5·7] for chemotherapy alone vs 4·4 months [4·2–5·5] for chemotherapy plus cetuximab, p=0·32) with increased rates of drug-related adverse events. In the second trial, REAL3,6 553 patients with advanced oesophagogastric cancer were randomly allocated to receive chemotherapy (epirubicin, oxaliplatin, and capecitabine) or reduced-dose chemotherapy plus panitumumab. Unexpectedly, addition of panitumumab to chemotherapy signifi cantly reduced median overall survival from 11·3 months (95% CI 9·6–13·0) with standard dose chemotherapy to 8·8 months (7·7–9·8) with panitumumab plus chemotherapy.

To interpret the unexpected results of these two studies, we can learn from the studies of targeted therapy with anti-EGFR antibodies for metastatic colorectal cancer. FOLFIRI (infusional fl uorouracil, irinotecan, and leucovorin), FOLFOX (infusional fl uorouracil, oxaliplatin, and leucovorin), and CapeOx (capecitabine plus oxaliplatin) are all established front-line regimens for treatment of advanced colorectal cancer. The addition of cetuximab to FOLFIRI reduced the risk of progression of colorectal cancer, although no signifi cant diff erence was noted in overall survival and the benefi t of cetuximab was restricted to patients with KRAS wild-type tumours.7 Similarly, addition of panitumumab to FOLFOX signifi cantly improved PFS and suggested an improvement (albeit not statistically signifi cant) of overall survival in patients with KRAS wild-type colorectal cancer, whereas panitumumab reduced PFS and median overall survival in individuals with mutations in KRAS.8 The Medical Research Council COIN trial9 investigated whether addition of cetuximab to FOLFOX or CapeOx could improve PFS and overall survival in 1630 patients with advanced colorectal cancer, in which the choice

of chemotherapy was made according to local hospital policy or patient preference. In that trial, the overall eff ect of cetuximab was disappointing even in patients with KRAS wild-type tumours with regard to PFS and overall survival, but improved PFS with cetuximab was noted in individuals treated with FOLFOX. In addition to these fi ndings, COIN showed that overall survival was reduced in patients who had mutations in any of KRAS, BRAF, or NRAS, irrespective of treatment received. If these fi ndings can be translated into gastric cancer settings, use for anti-EGFR antibody should be restricted to patients with KRAS wild-type tumours, although unlike colorectal cancer, KRAS mutation seems to be uncommon in gastric cancer and oral fl uoropyrimidine seems to be a suboptimum partner of anti-EGFR antibodies. EGFR expression in colorectal cancer did not correlate with anti-tumour eff ectiveness of cetuximab in the COIN trial.9 Analysis of data from another randomised phase 3 trial10 suggested no association between EGFR expression level and treatment eff ect. These fi ndings suggest that HER2 might be involved in signal transduction of the EGFR pathway. In the EXPAND trial,5 patients with HER2-positive tumours generally had longer overall survival and an improved tumour response compared with individuals with HER2-negative tumours. Targeting of both EGFR and HER2 with dual inhibitors such as lapatinib might be eff ective for EGFR and HER2 double-positive gastric cancers. Ongoing phase 3 trials will elucidate the role of lapatinib in the treatment of gastric cancer. More stringent selection of patients with specifi c biomarkers amenable to a targeted therapy could lead to the success of the trial. Although the EXPAND5 and REAL36 trial resulted in negative fi ndings, ongoing analysis of biomarkers in both trials might be of use, which will benefi t our patients in the future.

Tetsuji FujitaDepartment of Surgery, Jikei University School of Medicine, Tokyo 105-8461, Japantetsu@jg8.so-net.ne.jp

I declare that I have no confl icts of interest.

1 Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687–97.

2 Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16: 15–31.

3 Terashima M, Kitada K, Ochiai A, et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in Stage II/III gastric cancer. Clin Cancer Res 2012; 18: 5992–6000.

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4 Kim NA, Lee HS, Lee HE, et al. EGFR in gastric carcinoma: prognostic signifi cance of protein overexpression and high gene copy number. Histopathology 2008; 52: 738–46.

5 Lordick F, Kang Y-K, Chung H-C, et al, on behalf of the Arbeitsgemeinschaft Internistische Onkologie (AIO) and Expand Investigators. Capecitabine and cisplatin with or without cetuximab for patients with with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013; published online April 15. http://dx.doi.org/10.1016/S1470-2045(13)70102-5.

6 Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 2013; published online April 15. http://dx.doi.org/10.1016/S1470-2045(13)70096-2.

7 Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408–17.

8 Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fl uorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as fi rst-line treatment in patients previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28: 4697–705.

9 Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based fi rst-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2103–14.

10 Licitra L, Storkel S, Kerr KM, et al. Predictive value of epidermal growth factor receptor expression for fi rst-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer 2012; published online Dec 19. DOI:10.1016/j.ejca.2012.11.018.

Published OnlineMarch 27, 2013

http://dx.doi.org/10.1016/S1470-2045(13)70097-4

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Arm lymphoedema after breast cancerBreast-cancer-related lymphoedema is a substantial problem in women after they have undergone breast cancer treatment. Despite the introduction of breast-conserving surgery and minimal lymphatic intervention (eg, sentinel-lymph-node biopsy [SLNB]), incidence rates remain disappointingly high. In The Lancet Oncology, Tracey DiSipio and colleagues1 report the fi ndings of their systematic review and meta-analysis in which they shown that roughly one in fi ve women with breast cancer will develop arm lymphoedema.1 The incidence was four times higher in women undergoing axillary lymph-node dissection compared with those who received sentinel-lymph-node biopsy.

Lymphoedema is the accumulation of lymph in the interstitial spaces caused by the failure of the lymph-conducting system (lymph and lymph glands) to absorb or transport lymph back to the blood circulation.2 The drainage basin of the axillary lymph glands is the ipsilateral breast, upper quadrant of the trunk, and the upper limb. Consequently, any disruption to lymph fl ow through the axilla can result in lymphoedema in any part of the drainage basin. With breast conservation rather than mastectomy as standard treatment, breast lymphoedema has become much more of a clinical problem but has received much less research attention. Because breast lymphoedema can occur without arm swelling, the overall incidence of breast cancer-related lymphoedema within the forequarter is probably higher than data for arm swelling alone suggest.

The pathophysiology of breast cancer-related lymphoedema is complicated. Although interference with lymph drainage routes is fundamental to its development, the exact mechanisms leading to swelling

are poorly understood. In view of the consistency of treatment protocols for breast cancer, some clinical questions remain unanswered. Why do most women not develop breast cancer-related lymphoedema? Why can such lymphoedema develop either immediately or many years after having breast cancer? Why is the distribution of swelling in the arm non-uniform (eg, a patients’ forearm can be swollen but not their hand)? If lymphatic obstruction post-surgery is the cause, then the whole upper limb could be expected to be aff ected, but this is often not the case.

Findings from studies done since 2009 have shown that after axillary surgery and before the onset of oedema, women who later develop breast cancer-related lymphoedema have higher lymph fl ows (and not lower as one might expect) than women who do not develop lyphoedema.3 Lymph fl ow is also increased in the contralateral arm, indicating axillary surgery has a systemic not just a regional eff ect.3,4 Furthermore, lymphatic pump failure develops in established breast cancer-related lymphoedema.5 One hypothesis is that an as-yet-unidentifi ed subgroup of women with higher lymph fl ows develop such lymphoedema because of the chronically increased lymph load working against increased lymphatic outfl ow resistance, which then causes lymphatic pump failure.6

DiSipio and colleagues identifi ed obesity and more extensive surgery as risk factors lent support by strong evidence. Whereas more extensive surgery as a prognostic factor is understandable, the relation between obesity and arm lymphoedema is more complex. A functional link has emerged between lymphatic malfunction and the pathogenesis of