Review

Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review
Scott A Laurie, Alan L Ho, Matthew G Fury, Eric Sherman, David G Pster

Adenoid cystic carcinomas (ACC) are rare cancers usually arising in the salivary glands. Once metastatic, the natural history can vary; some patients with indolent cancer remain asymptomatic for long periods, whereas others have rapidly progressive disease. Chemotherapy is generally reserved for the palliative treatment of symptomatic locally recurrent or metastatic disease that is not amenable to further surgery or radiation. Prospective trials of chemotherapy in advanced ACC are limited, and the optimum regimen is unclear. The aim of this systematic review is to summarise and rate the quality of trials assessing chemotherapy for treatment of ACC, by use of the European Lung Cancer Working Party scoring system. Endpoints evaluated include tumour response and rates of symptomatic improvement. 34 trials involving 441 patients are included. We give evidence-based recommendations for management of ACC with chemotherapy, along with considerations for the design of future clinical trials in this disease.

Lancet Oncol 2011; 12: 81524 Published Online December 13, 2010 DOI:10.1016/S14702045(10)70245-X Ottawa Hospital Cancer Centre, Division of Medical Oncology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada (S A Laurie MD); and Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Weill Medical College, Cornell University, New York, NY, USA (A L Ho MD, M G Fury MD, E Sherman MD, Prof D G Pster MD) Correspondence to: Dr Scott A Laurie, Ottawa Hospital Cancer Centre, 501 Smyth Road , Ottawa, Ontario, K1H 8L6 Canada slaurie@ottawahospital.on.ca

Introduction
Adenoid cystic carcinomas (ACC) are rare variants of adenocarcinoma that most often arise in the salivary glands, and account for 25% of malignant tumours in the major salivary glands1 and 50% in the minor glands.2 Roughly 500 new cases of ACC of the head and neck are diagnosed in the USA each year.3 Very rarely, ACC can originate at other sites, such as the trachea, lung, breast, skin, cervix, Bartholins glands, and oesophagus. The natural history of ACC is best described for tumours of salivary origin: 10-year overall survival for patients is about 50%, but locoregional and distant recurrence after a short disease-free interval are common.4,5 Once metastatic disease is present, case series of salivary ACC suggest that the median duration of survival is about 3 years.4,6 Up to 10% of these patients survive for more than 10 years,5,7 consistent with an indolent growth history in some patients; however, more rapidly progressive disease can occur, and one-third of patients die within 2 years of developing metastases.7 Ultimately, most patients with recurrent disease die from their cancer, highlighting the need for eective therapies. The toxic eects of palliative treatment should be carefully weighed against the fact that many patients have indolent disease that can cause few symptoms for several years. Because of the rarity of ACC, there are few clinical trials investigating the ecacy of systemic therapy. The aim of this systematic review is to qualitatively assess studies of systemic therapy for recurrent or metastatic ACC, to develop recommendations for management of patients, and to discern how these experiences might inform future clinical trials in this disease.

Methods
Search strategy and selection criteria
We did a systematic search of Medline (January, 1966, to September, 2009), Cancerlit (January, 1975, to October, 2002), Old Medline (January, 1950, to December, 1966), and the Cochrane Library (2007, issue 3). The medical
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subject heading Carcinoma, adenoid cystic was combined with the following terms: cylindroma, salivary gland neoplasms, breast neoplasms, lung neoplasms, tracheal neoplasms, vulvar neoplasms, otorhinolaryngologic neoplasms, cervix uteri, antineoplastic agents, antineoplastic combined chemotherapy protocols, clinical trial, phase II, randomized controlled trial, and review article. Relevant articles, abstracts, and review articles were selected and reviewed, and the reference lists from these sources were searched for additional trials. Proceedings of the annual meetings of the American Society of Clinical Oncology, the European Society of Medical Oncology, and the European Cancer Conference from 1990 onwards were hand searched for relevant abstracts, then a search for a fully published manuscript was done. The Physician Data Query (PDQ) clinical trials database was searched for relevant ongoing trials. The last search was done April 1, 2010. Only trials published in English in peer-reviewed journals were included. Studies were eligible if they were phase 2 or 3 trials of systemic therapy in metastatic or unresectable locoregional ACC of any primary site, or of any primary site where more than 25% of patients had ACC histology and for which the results for those patients were presented separately. Retrospective reviews were also considered. In cases where an abstract or manuscript was reported once and then updated, with or without additional enrolled patients, the most recent publication was used. Phase 1 trials and case reports of individual patients were not included. Whenever possible, investigators were contacted for additional information. Our research began before publication of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews, thus no formal written review protocol was generated. In some cases, it was dicult to determine whether results were from a prospective clinical trial with a

For the Physician Data Query clinical trials database see http://cancer.gov/clinicaltrials/ nding

For the PRISMA guidelines for systematic reviews see http://www.plosmedicine.org/ article/info%3Adoi%2F10. 1371%2Fjournal.pmed.1000097

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Panel: Components of the European Lung Cancer Working Party methodology score for phase 2 trials Internal validity (scientic quality) Patient selection criteria (eg, age, performance status, histology, prior therapy) Method of registration Description of patient work-up before, during, and at completion of therapy Description of outcomes (eg, response rates and duration, survival, toxic eects) Trial objectives and statistical methods External validity (generalisability) Description of experimental intervention Description of characteristics of, and an accounting of all, enrolled patients Antitumour activity Survival data Description of toxicity of experimental intervention
Each component of the checklist has several subcomponents, which are assigned a score of 02, depending on the presence and clarity of information. A score of 0100 is generated, with a higher score indicating higher methodological quality.

63 possibly relevant publications or abstracts identied and screened for eligibility

25 studies excluded 4 with no, or too few, patients with ACC 2 of chemoradiation for localised disease 6 for which data on ACC patients were not presented separately 4 manuscripts subsequently updated and published 9 abstracts subsequently updated and fully published

1 study could subsequently be included as the corresponding author kindly provided unpublished data9

39 eligible studies identied

5 institutional retrospective reviews of patients treated with various therapies not necessarily on a clinical trial1014

predened protocol, or from a case series of patients who received similar treatment but without a dened protocol. A report was classied as a phase 2 trial if all patients received the same therapy (including predetermined dose adjustments for toxicity and had the same mandated response assessments) and it met any of the following criteria: mention of approval by an institutional review board; mention of predened objectives or statistical considerations for declaring a treatment active; or was done under the auspices of a cooperative group. A paper was classied as a case series if this was stated in the manuscript, if patients received heterogeneous treatments, or if the study did not clearly meet the criteria for classication as a phase 2 trial.

34 studies included in analysis (4 studies only in abstract form,17,20,21,30 30 studies suitable for methodological assessment) 22 classied as true prospective phase 2 trials9,1535 12 classied as case series10,3646

Figure: Flowchart of study selection ACC=adenoid cystic carcinoma.

Results
Study selection
A owchart of the study selection process is shown in the gure. Of the 34 studies included in our analysis, 22 were classied as reporting results of prospective phase 2 trials9,1535 and the other 12 were case series.10,3646 There were 23 studies of single agents or combination cytotoxic chemotherapy regimens,9,10,18,19,22,24,27,29,3143,45,46 one randomised phase 2 trial comparing a single agent with a combination cytotoxic chemotherapy regimen,16 and ten studies of targeted agents: one each of getinib,20 cetuximab,26 lapatinib,15 and bortezomib,17 and six of imatinib, either alone21,23,25,28,44 or in combination with cisplatin.30 No phase 3 trials were found. All trials apart from one23 enrolled patients with ACC of salivary gland origin only.

Data analysis
The primary outcome of interest was antitumour activity, as measured by reported objective responses. No attempt was made to standardise response criteria across studies. Other outcomes considered were rates of disease stabilisation, symptom improvement, and survival. The methodological quality of a trial was assessed using the scoring system of the European Lung Cancer Working Party (ELCWP; panel).8 Only prospective trials or case series (not retrospective reviews or abstracts) are assessable by this scale, which assesses the internal (scientic) validity and the external validity (generalisability) of a study. A score between 0 and 100 is generated, with a higher score indicating higher methodological quality. Data were extracted by SAL and ALH, and discrepancies were resolved by consensus.
816

Methodological assessment
30 studies were assessable with the ELCWP scale for scoring quality, and the overall median score was 55 (range 2285). Reports of phase 2 results had a higher median score (63, range 4085) than those classied as case series (395, range 2263). Quality tended to improve over time: of 13 manuscripts published since 2000, the median trial score was 68 (range 4485), compared with a median of 42 (range 2267) for those published earlier. With respect to internal validity, lack of explicit eligibility criteria, methods used for assessment of toxicity, and the
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Review

Drug

Patient characteristics (ACC patients only) N N with ACC 10 Symptomatic, Prior systemic progression, therapy or both NS NS N with distant metastases 6

Ecacy (ACC patients only) Objective responses (duration) 7 of 10 (NS) Stable disease (duration) NS Comments Median survival (months) NS Subjective relief of pain in 7 of 10; unclear if these were also those with objective response Partial response duration 3, 7, 13, 13 months

ELCWP score

Schramm et al36 Mattox et al27* Verweij et al35* Vermorken et al34*

Cisplatin 80100 mg/m2 every 46 weeks Mitoxantrone 12 mg/m2 every 3 weeks Mitoxantrone 14 mg/m2 every 3 weeks

10

22

18 32

18 32

NS Required (either) Required (both)

12 of 18 No

13 24

1 of 18 (19 months)

12 of 18 (518 months)

19 18

48 63

4 of 32 22 of 32 (313 months) (2530 months) 2 of 20 (75 and 20 months) 0 of 21 2 of 13 (5 and 8 months) 0 of 14 (NS) NS

20 Epirubicin 30 mg/m2 weekly; if no response, 90 mg/m2 every 3 weeks

20

3 of 20

14

14

Symptom improvement in 30% 67

Van Herpen Gemcitabine 1250 mg/m2 21 et al32* days 1 and 8 every 3 weeks Licitra et al46 Gilbert et al19* Airoldi et al16* Cisplatin 25 100 mg/m2 every 3 weeks Paclitaxel 200 mg/m2 (3 hours) every 3 weeks Vinorelbine 30 mg/m2 weekly 50

21 13 14

Required (either) NS NS

No 6 of 25 (NS for ACC) No

NS 7 of 13 13 of 14

11 of 21 (NS) 6 of 13 (NS) 7 of 14 (NS)

NS 20 25

Stable disease of at least 6 months in 10 patients

72 47 85

20

13

Required (progression)

3 of 20 (NS for ACC)

7 of 13

2 of 13 (NS)

6 of 13 (NS)

NS

No response in patients previously treated. Subjective relief of pain in responders

60

ACC=adenoid cystic carcinoma. ELCWP=European Lung Cancer Working Party. N=number of patients. NS=not stated. *Considered true phase 2 trial. One group of a randomised phase 2 trial.

Table 1: Studies of single agents in adenoid cystic carcinoma

timing and components of patient assessment before, during, and after investigational therapy were common reporting deciencies. Many trials did not state an objective, and only seven15,19,23,24,26,28,32 reported an a priori determination of sample size. Deciencies in external validity included poor or absent data for toxicity, and incomplete reporting of outcomes such as survival and duration of response or disease stabilisation. Only 14 reports9,15,16,18,19,2326,28,29,32,34,44 explicitly mentioned informed consent or approval by an institutional review board. Baseline characteristics were very heterogeneous between studies, particularly the proportion of patients with distant metastases versus only locoregional disease, and numbers and types of prior systemic therapies. Studies also varied greatly in the requirement for documented disease progression or disease-related symptoms at study entry. Even when these were required, reports often failed to clearly delineate the methods by which disease progression or disease-related symptoms were documented, or the time period in which these events were required to have occurred before study enrolment.

provided. Single-agent intra-arterial cisplatin led to objective responses and symptom relief in four patients,14 whereas intravenous cisplatin, given at various doses and schedules in another study, did not lead to any objective responses in ten patients.10 A study published in 198411 combined several institutions experiences with systemic therapy for ACC, with a review of all case reports to date, including three of the studies mentioned above1214 and an additional case series of single-agent cisplatin.36 In summarising response data for all 65 patients with ACC reported in the literature as of 1984, the investigators reported activity for single-agent cisplatin (response rate 59%), doxorubicin (42%), uorouracil (46%), and doxorubicin-containing combination regimens (60%).11

Activity of single-agent standard cytotoxic drugs

Of eight trials of single-agent standard cytotoxic drugs, ve were restricted to patients with ACC (table 1).27,32,3436 Few patients received prior systemic therapy, apart from in one trial of mitoxantrone.27 About one-third of patients had locoregionally recurrent disease without distant metastases. Single-agent mitoxantrone,27,35 cisplatin,36,46 epirubicin,34 vinorelbine,16 paclitaxel,19 and gemcitabine32 were studied in 141 patients. Objective major responses were uncommon (18 of 141), with none observed in the 14 patients who received paclitaxel19 or the 21 patients who received gemcitabine.32 No responses were seen in
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Data from retrospective reviews

Two studies detailing institutions experiences with chemotherapy for ACC12,13 reported antitumour activity with single-agent uorouracil, doxorubicin, and hexamethylmelamine; no treatment details were
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previously treated patients. Reported response durations ranged from 5 to 20 months. Stable disease was more common than objective responses, and was reported in 64 of 111 patients.16,19,27,32,35,46 Disease stabilisation might be a marker of antitumour activity, but this is dicult to interpret unless clear evidence of progression is documented before the start
Regimen Patient characteristics (ACC patients only) N N with ACC 11 Symptomatic, progression, or both Required (symptoms) NS Prior systemic therapy 2 of 11 N with distant metastases 9 of 11

of therapy. Notable rates of disease stabilisation (in 39 of 66 patients) were also seen in trials which required progressive or symptomatic disease for study entry, specically those investigating mitoxantrone,35 vinorelbine,16 and gemcitabine.32 Duration of disease stabilisation was reported only in the two mitoxantrone trials and varied greatly.
ELCWP score Comments Median survival (months) 12 Symptom improvement in 7 of 11 despite no objective responders 51

Ecacy (ACC patients only) Objective responses (duration) 0 of 11 Stable disease (duration) 9 of 11 (NS)

Hill et al22*

P: 100 mg/m2 day 1 F: 1 g/m2 daily x 4 Both every 4 weeks

11

De Haan P: 20 mg/m2 days 15 et al10 A: 50 mg/m2 day 1 B: 30 mg days 15 All every 3 weeks Triozzi et al31* C: 1000 mg/m2 day 1 Vn: 1 mg days 1, 4 F: 750 mg/m2 daily x 4 All every 4 weeks P: 60 mg/m2 E: 50 mg/m2 F: 200 mg/m2 daily All every 3 weeks C: 450 mg/m2 A: 45 mg/m2 Both day 1 every 3 weeks

1 of 9

8 of 9

3 of 9 (6, 21, 77 months)

5 of 9 (324 months)

67

39

NS

No

6 of 8

2 of 8 (NS)

4 of 8 (NS)

NS

Symptom improvement in both 40 responders and in some without objective response 2 patients given Cb (AUC=5) at start of cycle 1 instead of P; neither responded 61

Ross et al29*

All were progressive

1 of 8

5 of 8

1 of 8 (34 months)

5 of 8 (416 months)

27

Posner et al37

14

NS

No

4 of 5

2 of 5 (2, 8 months) 3 of 9 (NS)

NS

38

Dreyfuss C: 500 mg/m2 et al38 A: 50 mg/m2 P: 50 mg/m2 All day 1 every 4 weeks Belani et al39 C: 400 mg/m2 A: 40 mg/m2 P: 60 mg/m2 All day 1 every 35 weeks

13

NS

3 of 13 (NS for ACC) No

NS

NS

NS

2 responders with ACC had localised disease

31

NS

2 of 4

1 of 4 (16 months)

NS

NS

Response in patient with localised disease

29

Tsukuda C: 400 mg/m2 et al40 Pr: 40 mg/m2 P: 60 mg/m2 All day 1 every 4 weeks Creagan CAP: various et al41 Licitra et al45 C: 500 mg/m2 A: 50 mg/m2 P: 50 mg/m2 All day 1 every 3 weeks C: 500 mg/m2 day 1 A: 50 mg/m2 day 1 P: 40 mg/m2 days 2, 3 F: 500 mg/m2 days 1,2 All every 34 weeks P: 60 mg/m2 E: 50 mg/m2 F: 600 mg/m2 All day 1 every 3 weeks P: 50 mg/m2 A: 30 mg/m2 F: 500 mg/m2 All days 1, 8 every 4 weeks

14

NS

No

NS for ACC

2 of 6 (NS)

NS

NS

Only 23 courses planned for all patients

42

34

11

NS

4 of 34 (NS for ACC) 3 of 22 (NS for ACC) No

NS

2 of 11

NS

NS

40

22

12

Required (both)

8 of 12

3 of 12 (partial response 5, 9, 13 months) 3 of 7 (24, 52, 72 weeks)

5 of 12 (NS)

34

29

Dimery et al18*

17

NS

4 of 7

4 of 7 (NS)

30

63

Airoldi et al42

NS

No

3 of 4

2 of 4 (9 and 13 months)

0 of 4

10

Subjective relief of pain reported in responders

59

Venook et al33*

17

NS

1 of 9

4 of 9

2 of 9 (PR NS)

2 of 9 (NS)

16

3 patients with ACC received PAF as induction therapy without response

49

(Continues on next page)

818

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Review

Regimen

Patient characteristics (ACC patients only) N N with ACC 9 Symptomatic, progression, or both Required (progression) Required (progression) Prior systemic therapy 2 of 16 (NS for ACC) 8 of 14 (NS for ACC) 0 of 11 N with distant metastases NS for ACC (9 of 16 overall) NS for ACC (13 of 14 overall) 7 of 11

Ecacy (ACC patients only) Objective responses (duration) 4 of 9 (NS for ACC) 2 of 10 (5 and 12 months) Stable disease (duration) Comments Median survival (months) NS No response in 2 previously treated patients Subjective relief of pain reported in responders. No response in any previously treated patients

ELCWP score

(Continued from previous page) Airoldi et al16* Airoldi et al43 P: 80 mg/m2 day 1 V: 25 mg/m2 days 1, 8 Both every 3 weeks Cb: AUC 55 T: 175 mg/m2 (3 hours) All day 1 every 3 weeks 16 NS 60

14

10

NS

NS

63

Gedlicka P: 30 mg/m2 days 13 et al9* M: 12 mg/m2 day 1 All every 3 weeks Laurie et al24* G: 1000 mg/m2 days 1, 8 P: 70 mg/m2 day 2 or Cb: AUC 5 day 1 All every 3 weeks

14

11

NS

1 of 11 (50 months) 2 of 10 (NS)

8 of 11 (918 months) NS

48

68

33

10

Not required for ACC

5 of 33 (NS for ACC)

NS

NS

85

ACC=adenoid cystic carcinoma. ELCWP=European Lung Cancer Working Party. N=number of patients. P=cisplatin. F=uorouracil. NS=not stated. A=doxorubicin. B=bleomycin. C=cyclophosphamide. Vn=vincristine. E=epirubicin. Cb=carboplatin. AUC=area under the curve. Pr=pirarubicin. V=vinorelbine. T=paclitaxel. M=mitoxantrone. G=gemcitabine. *Considered true phase 2 trial. One group of a randomised phase 2 trial. Contains additional information obtained from corresponding author not reported in manuscript. Stable disease lasted at least 16 months (ie, it was still ongoing when reported).

Table 2: Studies of combination chemotherapy in adenoid cystic carcinoma

ELCWP scores were lowest for reports of cisplatin.36,46 Scores ranged up to 85 for the other drugs studied, with the highest score achieved by a cooperative group trial of paclitaxel.19

Activity of standard cytotoxic drugs in combination

The activity of standard cytotoxic drugs given in combination was studied in 143 patients enrolled in 17 trials, four of which were restricted to patients with ACC (table 2).10,22,29,31 Less than 15% of patients had prior systemic therapy. By contrast with single-agent studies, most patients had distant metastases. Cisplatin and doxorubicin were the most common drugs given in combination regimens, and were given with cyclophosphamide (CAP regimen) in four trials.38,39,41,45 Although the trials assessing CAP regimen used slightly dierent doses and schedules, major objective responses were noted in nine of 36 patients (response rate 25%; 95% CI 1139%). Regimens containing both cisplatin and an anthracycline other than doxorubicin also showed modest activity,29,40,42 as did other platinum-based regimens.9,16,24,43 In 14 studies, cisplatin-based regimens led to objective responses in 29 of 118 patients (response rate 25%, 1733%). Response duration ranged widely, from 6 to 77 months. Experience with carboplatin-based regimens has been even more limited: a study of carboplatin plus paclitaxel reported a response rate of 20% (two of ten patients),43 and two studies reported that all seven patients who received carboplatin instead of planned cisplatin did not respond to therapy.24,29 Disease stabilisation in patients who had been progressing was reported in trials of cisplatin-based therapy.22,29,45 Duration
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of disease stabilisation for patients with ACC given any regimen was reported in only two trials.9,10 In two studies,16,43 none of the previously treated patients responded to trial therapy. A randomised phase 2 trial comparing cisplatin plus vinorelbine to single-agent vinorelbine16 included only 36 patients (22 with ACC), and was therefore underpowered to conclude that the combination is better. The combination was associated with greater toxicity, particularly nausea, vomiting, myelosuppression, and neuropathy.

Activity of imatinib
High expression of c-kit has been noted in up to 90% of ACC tumours.47 Six studies have assessed imatinib activity in ACC, with only two objective responses reported in 71 evaluable patients (table 3).21,23,25,28,30,44 Both responses were stable (durations of 14 months and at least 15 months) and occurred in the only study that required high c-kit expression and progressive disease for study entry.21 Stable disease was reported more commonly than objective responses, however, evidence of disease progression at study entry was either not required or not stated in most trials. One trial did explore the ecacy of imatinib in combination with cisplatin:30 patients received imatinib alone for 2 months, and those who did not respond or progressed were also given cisplatin. Of 17 evaluable patients, two patients progressed and no objective responses were observed during the imatinib-alone phase. With the addition of cisplatin, three partial responses were noted.
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Dose

Patient characteristics (ACC only) N Symptomatic, Prior systemic therapy progression, or both Not required Required (progression) 8 of 16 eligible patients NS N with distant metastases NS NS

Ecacy (ACC only) Objective responses 0 of 15 0 of 17 (to imatinib) Stable disease 9 of 15 Median survival (months) 7 Comments

ELCWP score

Hotte et al23* Slevin et al30*

400 mg by mouth twice daily

15

No clear correlation between stable disease and c-kit IHC 2 PD after imatinib alone; 3 PR (in 15 patients) with combination cisplatin and imatinib Only patients with c-kit-positive tumours enrolled Rapid progression in 2 patients on therapy 3 of 4 patients positive for c-kit by IHC Only patients with highly expressing c-kit-positive tumours enrolled

81 Not assessable (abstract)

17 800 mg daily for 2 months; patients with stable disease then received cisplatin 80 mg/m2 every 3 weeks in addition to imatinib 400 mg daily 400 mg daily, with escalation up to 800 mg in 4 patients 400 mg by mouth twice daily 400 mg by mouth daily 400 mg by mouth twice daily 10 4 4 21

15 of 17 NS (to imatinib)

Pfeer et al28* Lin et al25* Ochel et al44 Guigay et al21*

NS NS NS Required (progression)

5 of 10 4 of 4 2 of 4 9 of 21

6 of 10 4 of 4 4 of 4 19 of 21

0 of 10 0 of 4 0 of 4 2 of 21 (duration 14 and 15 months)

2 of 10 1 of 4 1 of 4 6 of 21

NS 6 NS NS

44 61 44 Not assessable (abstract)

ACC=adenoid cystic carcinoma. ELCWP=European Lung Cancer Working Party. N=number of patients. NS=not stated. IHC=immunohistochemistry. PD=progressive disease. PR=partial response. *Considered true phase 2 trial. Additional data obtained from reference 48. Objective response was still ongoing at 15 months when reported. 16 patients enrolled of which 15 were evaluable for response.

Table 3: Studies of imatinib in adenoid cystic carcinoma

Activity of other targeted agents

Studies of other targeted agents in ACC are summarised in table 4. Expression of the epidermal growth factor receptor (EGFR) in ACC of salivary origin has been reported.49 Phase 2 studies of the EGFR inhibitors getinib20 (19 patients) and cetuximab50 (23 patients) did not report any major objective responses. Disease stabilisation was reported with both drugs; however, not all patients had progressive disease at the time of study entry. Lapatinib, a dual inhibitor of EGFR and HER2 (also called ERBB2), was studied in 19 patients who had documented radiological progression, symptomatic deterioration, or both, within 6 months of study entry.15 Immunohistochemistry evidence of expression of either target was required. No objective responses were seen, although nine patients (47%) had disease stabilisation for at least 6 months. The proteasome inhibitor bortezomib has been studied in 25 patients.17 Eligible patients had evidence of disease progression within the previous 9 months. Bortezomib was given until disease progression, at which time doxorubicin was added, given weekly for two of three weeks. No objective responses were reported with singleagent bortezomib, but 17 patients had disease stabilisation, with a median progression-free survival of 85 months. One objective response was seen with the addition of doxorubicin. Overall, therapy was well tolerated.

single-agent chemotherapy,19,27,34,35,46 and from 8 to 67 months in nine trials assessing combination chemotherapy.9,10,18,22,29,33,37,42,45 In general, survival was shorter in cohorts in which almost all patients had distant metastases (median 11 months; 667 months), as opposed to trials in which a substantial proportion of patients had only locoregional disease (median 195 months; 1448 months). No study had a formal quality-of-life assessment. Seven trials reported symptom improvement with therapy, as determined by subjective pain relief or a decrease in analgesic use. No study described the method used to quantify symptom improvement. Symptom improvement was seen with single agents34,36 and combination chemotherapy.16,22,31,43 For the most part, this benet was limited to responders,16,42,43 although the rate of symptomatic improvement was greater than the objective response rate with single-agent epirubicin34 and in two studies of combination chemotherapy.22,31

Discussion
Overview of the evidence
In publications spanning more than 20 years, outcomes of systemic therapy in advanced ACC have been reported in less than 500 patients. Most trials were small and did not have a predetermined sample size, and since many were done at a single institution, took several years to accrue. No studies of combination regimens enrolled more than 12 patients with ACC. Most regimens have been assessed only once, and for those that have been investigated in more than one study, dierences in drug dose or schedule
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Eects of systemic therapies on other endpoints

In the studies we reviewed, median overall survival varied widely and was not consistently reported. Median overall survival ranged from 14 to 25 months in ve studies of
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Drug studied

Patient characteristics (ACC only) N N with ACC 19 Symptomatic, progression, or both Required (progression) Not required; documented in 11 of 23 with ACC Required (either) Required (progression) N with Prior systemic distant therapy metastases NS Most

Ecacy (ACC only) Objective responses 0 of 19 Stable disease Median survival (months) NS Comments

ELCWP score

Glisson et al20* Locati et al26* Agulnik et al15* Argiris et al17*

Getinib 250 mg by mouth daily Cetuximab 400 mg/m2 loading dose then 250 mg/m2 IV weekly Lapatanib 1500 mg by mouth daily

28

13 of 19 (median duration 13 weeks)

Not assessable (abstract)

30

23

13 of 23

22 of 23

0 of 23

NS 20 of 23 (median duration 6 months, range 115) 15 of 19 Not reached NS

74 All 11 with ACC and PD at study entry had stable disease for 6 months or longer 9 of 19 with stable disease >6 months Median PFS 35 months Median time to progression 85 months 1 partial response with addition of doxorubicin 78

39

19

9 of 19

17 of 19

0 of 19

Bortezomib 13 mg/m2 days 25 1, 4, 8, 11 every 3 weeks; at PD, doxorubicin 20 mg/m2 added days 1, 8

25

10 of 25

All

0 of 25

17 of 25

Not assessable (abstract)

ACC=adenoid cystic carcinoma. ELCWP=European Lung Cancer Working Party. N=number of patients. NS=not stated. IV=intravenous. PFS=progression-free survival. PD=progressive disease. *Considered true phase 2 trial.

Table 4: Studies of other targeted agents in adenoid cystic carcinoma

make data interpretation dicult. The ability to compare results across studies is limited, given the heterogeneity of the populations studied and the methodological quality of these trials, which was generally suboptimum. The ELCWP scoring system is a checklist that assesses the quality of phase 2 trials. All such systems evaluate similar key components, and the results generated with the ELCWP scale in this review would likely be reproduced with other checklists. Although the ELCWP score is a qualitative measure and subject to interobserver dierences, it was applied in a systematic and consistent way for all trials in this analysis, so that relative dierences in scores reliably reect discrepancies in methodological quality. This assessment of quality is a crucial component of our analysis, since phase 2 trials of poorer methodological quality are more likely to produce positive results than those with more rigorous design.51 Indeed, studies with ELCWP scores at or below the median value reported 30 objective responses in 139 patients (response rate 22%), whereas those with a score above the median reported 23 responses in 220 patients (response rate 105%). In this analysis, which encompasses a small dataset, such dierences could substantially skew the nal conclusions if recommendations were derived without consideration of methodological quality. The improvement in ELCWP scores over time shows a movement towards true prospective, protocol-dened clinical trials, thereby giving less weight to the earlier reports that were mainly case series of patients who received similar treatment. Finally, there are no data on whether metastatic ACC behaves dierently when it originates at sites other than the salivary glands. Outcomes with chemotherapy for ACC of other primary sites consists only of single-patient case reports. Although all the studies in this review address salivary ACC, without data suggesting distinct biological
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behaviour or response to chemotherapy, it is reasonable to extrapolate ndings from salivary ACC to ACC of dierent primary sites. These considerations were used to formulate the following conclusions and recommendations regarding the role of systemic therapy in the treatment of recurrent or metastatic ACC.

Antitumour activity
Major objective responses were infrequent. Although stable disease was more common, it is dicult to discern whether observed periods of stable disease reect drug activity or indolent biological behaviour of the disease. Reports of stable disease in trials involving patients with progressive disease could provide more convincing evidence that treatment alters the natural history of these tumours, particularly if there was rapid progression before therapy. Median survivals vary widely, likely because of the inclusion of patients with only locoregional recurrences and those with distant metastases; there is no clear correlation between survival and antitumour activity of drugs or regimens. Since it is unclear whether chemotherapy alters the natural history of ACC, the primary goal of systemic therapy is palliation of disease-related symptoms. Seven studies reported that therapy led to relief of pain, sometimes in patients who did not objectively respond. This result supports the practice of limiting chemotherapy to patients with disease-related symptoms or those who have rapidly progressive disease. Validated evaluation of symptom improvement might also be an informative ecacy endpoint in future clinical trials. Mitoxantrone has been studied in the greatest number of patients (including one trial of reasonable methodological quality), and might lead to disease stabilisation in those with progressive disease. Vinorelbine and epirubicin seem to have activity in those with progressive disease;
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Rationale Enrol homogeneous populations with respect to prior therapies and number and sites of metastases Improves comparison of ecacy across trials Trials of small numbers of heterogeneous patients do not provide conclusive evidence of ecacy (or lack of ecacy) Evidence supports limiting therapy to these patients Stabilisation of progressive disease suggests true therapeutic eect Responsiveness of ACC to therapies might be distinct from other histologies, particularly mucoepidermoid11,19 Maximise eciency of investigating new drugs in limited numbers of available patients

Limit enrolment to those with clearly progressive or symptomatic disease. Clearly dene how progression is measured and over what time period prior to enrolment Report results for ACC histology separate from other salivary histologies If objective response is the primary endpoint, use multistage statistical design with early stopping rules suggested single-agent response rate of 20% to declare drug as active in untreated patients any responses in previously treated patients suggests drug worthy of further study

Possible endpoints of disease stabilisation or symptom improvement in previously progressing patients. Objective responses are rare, whereas rates of disease stabilisation are higher and Use of validated quality-of-life scales for assessment of eects on disease-related symptoms symptom improvement might occur without fullling criteria for objective response Palliation of disease-related symptoms is key objective of therapy Multi-institutional or cooperative group setting for trials Hastens accrual, as in trials of imatinib23 and lapatinib15 Prevents duplication of trials

ACC=adenoid cystic carcinoma.

Table 5: Recommendations for clinical trial design in advanced adenoid cystic carcinoma

retrospective data also suggest that doxorubicin is an active drug. Paclitaxel is not recommended, based on a methodologically sound Eastern Cooperative Oncology Group (ECOG) phase 2 study that reported lack of activity in 14 patients with ACC.19 Gemcitabine has limited clinical activitydisease stabilisation was reported when the drug was given to patients with progressive disease32although mitoxantrone, vinorelbine, and epirubicin might be preferred since objective responses have been reported for these agents. Although objective responses have been reported with single-agent cisplatin, because of comparable ecacy with less toxic single agents, its routine use in the palliative setting is not recommended if single-agent therapy is chosen. Combination regimens containing cisplatin, typically in conjunction with an anthracycline, led to responses in no more than 33% of patients. Other platinum-based combinations have been studied in only a small number of patients with ACC and have yielded response rates with wide condence intervals; again, higher response rates were reported in trials with lower ELCWP scores. There are insucient data to support the routine substitution of carboplatin for cisplatin, or to conclude that combination cisplatin-based chemotherapy consistently leads to improved response rates and overall clinical benet compared with single agents. Singleagent therapy, therefore, remains an acceptable treatment strategy, particularly with the likelihood of increased toxic eects with combination therapies. The value of secondline therapy also remains unproven, since objective responses were not reported in patients who had received prior systemic therapy. Disappointing results reported from studies of imatinib suggest that c-kit expression alone is not a sucient predictor of response. However, among all the studies of targeted therapies in ACC, objective responses have only been observed with imatinib.21 These two responses were
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moderately durable and were seen in the one study that required strong c-kit positivity and disease progression for enrolment, suggesting that a subgroup of patients with ACC might benet from treatment with a c-kit inhibitor. Discoveries of uorescence in-situ hybridisation amplied c-kit and a recent report of c-kit mutations in ACC52 further argue that c-kit could be a relevant target for this disease. Two ongoing clinical trials are investigating novel c-kit inhibitors (dasatinib [NCT 00859937] and sunitinib [NCT00886132]). Data for other targeted therapies are limited and preliminary, and these drugs should not be routinely used outside a clinical trial, although lapatanib might be worthy of further study.

Implications for clinical trial design

Although ACC is rare, there is clearly a need for more high-quality clinical trials. The protracted course of the disease creates a higher prevalence of patients than is shown by incidence statistics, and suggests that identifying eective therapies could have a substantial eect for many patients. Many individuals with ACC are t, young, and highly motivated to learn more about their disease and to seek novel therapies, thus they are well suited to participation in clinical trials. Because of its rarity and highly varied natural history, it would be dicult to do a trial to assess whether chemotherapy improves survival in patients with recurrent ACC, therefore other endpoints, such as symptom improvement, need to be considered. Table 5 summarises recommendations for clinical trial design. Limiting enrolment to patients with progressive or symptomatic disease is important. How progression is assessed, and over what time period before enrolment, should be clearly dened in the protocol. This denition was often missing, and when present, varied widely between trials, hindering a comparison of the ecacy of agents with respect to disease stabilisation. Disease that is only slowly progressing before commencing study
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therapy might be classied as stable disease by response criteria, simply because sucient tumour enlargement had not occurred during the assessment period, whereas in fact the drug was having no eect on the natural history of the patients illness. The importance of prospective clinical trials is underscored by comparing response data from retrospective reviews with data from clinical trials. For example, retrospective reviews suggest response rates of 37% for single-agent cisplatin (ten of 27 patients) and 60% for anthracycline-containing regimens (six of ten patients), which are much higher than the 15% (two of 13 patients) and 30% (23 of 76 patients) response rates reported in clinical trials. Published case reports, and trials of poor methodological quality, might be inherently biased towards positive results and overestimate the true activity of a drug or regimen. Case reports and retrospective case series generate hypotheses but do not reliably predict the likelihood of benet from a treatment. Single-agent doxorubicin is listed as an active drug for ACC in oncology texts, although no prospective data exist to support its single-agent use. Likewise, hormonal therapies have been used anecdotally but there are no published prospective data. Hormone-receptor positivity is very rare in ACC of the breast53 or salivary glands,54 so hormonal therapies are unlikely to be successful. Although EGFR is expressed in a substantial proportion of ACC tumours, no drug against this target has led to major objective responses, possibly because of the rarity of activating mutations in the EGFR tyrosine-kinase domain in ACC.55 Expression of HER2 in ACC is varied. In a multicentre phase 2 trial of trastuzumab in patients with advanced salivary gland malignancies, only three of 70 patients with ACC who were screened for study entry overexpressed HER2,56 and neither of the two enrolled patients with ACC responded to therapy.57 The investigators concluded that trastuzumab is unlikely to have a main role in the treatment of ACC.57 These data highlight the importance of clinical trials in clarifying use of (often costly) drugs chosen based on a particular molecular target.

of rst-line therapy should be dictated by patient characteristics and comorbid conditions, toxicity concerns, patient preference, and cost. These therapies could be oered to suitable patients with metastatic ACC of other primary sites. In view of the modest activity of all standard agents, however, participation in an appropriate clinical trial is preferred. There are no convincing data to support the routine use of other cytotoxic, hormonal, or targeted agents, including agents targeting c-kit, outside of a clinical trial. After failure of rst-line chemotherapy, best supportive care or participation in a clinical trial (including phase 1 studies) are reasonable options.
Contributors SAL and DGP formulated the concept for the review. SAL and ALH did the literature search, data extraction, data analysis, writing, and editing. MGF and ES edited and reviewed the manuscript. DGP did the data analysis, writing, and editing. All authors approved the nal manuscript. Conicts of interest The authors declared no conicts of interest. Acknowledgments Supported in part by the Overman Fund. References 1 Renehan A, Gleave EN, Hancock BD, Smith P, McGurk M. Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre. Br J Surg 1996; 83: 175054. 2 Anderson JN Jr, Beenken SW, Crowe R, et al. Prognostic factors in minor salivary gland cancer. Head Neck 1995; 17: 48086. 3 Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston Park) 1998; 12: 67180. 4 Spiro RH, Huvos AG. Stage means more than grade in adenoid cystic carcinoma. Am J Surg 1992; 164: 62328. 5 Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck 2004; 26: 68192. 6 van der Wal JE, Becking AG, Snow GB, van der Waal I. Distant metastases of adenoid cystic carcinoma of the salivary glands and the value of diagnostic examinations during follow-up. Head Neck 2002; 24: 77983. 7 Spiro RH. Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg 1997; 174: 49598. 8 Meert AP, Berghmans T, Branle F, et al. Phase II and III studies with new drugs for non-small cell lung cancer: a systematic review of the literature with a methodology quality assessment. Anticancer Res 1999; 19: 437990. 9 Gedlicka C, Schull B, Formanek M, et al. Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies. Anticancer Drugs 2002; 13: 49195. 10 de Haan LD, De Mulder PH, Vermorken JB, Schornagel JH, Vermey A, Verweij J. Cisplatin-based chemotherapy in advanced adenoid cystic carcinoma of the head and neck. Head Neck 1992; 14: 27377. 11 Kaplan MJ, Johns ME, Cantrell RW. Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 1986; 95: 16570. 12 Tannock IF, Sutherland DJ. Chemotherapy for adenocystic carcinoma. Cancer 1980; 46: 45254. 13 Rentschler R, Burgess MA, Byers R. Chemotherapy of malignant major salivary gland neoplasms: a 25-year review of M D Anderson Hospital experience. Cancer 1977; 40: 61924. 14 Sessions RB, Lehane DE, Smith RJ, Bryan RN, Suen JY. Intra-arterial cisplatin treatment of adenoid cystic carcinoma. Arch Otolaryngol 1982; 108: 22124. 15 Agulnik M, Cohen EW, Cohen RB, et al. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol 2007; 25: 397884.

Search strategy and selection criteria These are described in detail in the Methods section.

Conclusion
Chemotherapy might have a palliative benet for a small proportion of patients with recurrent ACC of salivary gland origin who have progressive, symptomatic disease, after due consideration of other therapies (palliative radiation, metastatectomy of solitary lesions). Single-agent mitoxantrone or vinorelbine are both reasonable rst-line options, based on prospective clinical trial data that have shown objective responses in addition to stabilisation of disease, and a favourable toxicity prole. An anthracycline such as epirubicin is also a reasonable choice. For singleagent therapy, neither paclitaxel nor cisplatin are recommended because of lack of proven activity (paclitaxel) and availability of less toxic choices (cisplatin). If combination chemotherapy is chosen, available data support cisplatin and anthracycline combinations. Choice
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