A phase I study of OSI-211 and cisplatin as intravenous infusions given on days 1, 2 and 3 every 3 weeks in patients with solid cancers

M. J. MacKenzie1, H. W. Hirte1, L. L. Siu2, K. Gelmon3, M. Ptaszynski4, B. Fisher5 and E. Eisenhauer5,*

1 Hamilton Regional Cancer Centre, Hamilton, Ontario; 2 Princess Margaret Hospital, Toronto, Ontario; 3 Vancouver Cancer Centre, Vancouver, British Columbia, Canada; 4 OSI Pharmaceuticals, Boulder, CO, USA; 5 NCIC Clinical Trials Group, Kingston, Ontario, Canada

Received 12 September 2003; revised 13 November 2003; accepted 22 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

OSI-211 (also known as NX211) is a liposomal preparation of the topoisomerase I inhibitor, lurtotecan, which has shown antitumor activity in phase I and II clinical trials. Cisplatin is a widely used antineoplastic agent with activity in a broad range of tumor types. This phase I trial was conducted to determine the recommended doses of these agents, and their pharmacokinetic properties and toxicities in patients with advanced solid malignancies.

Patients and methods:

Fourteen patients with advanced and/or metastatic solid malignancies were enrolled in this trial. The first planned dose level was OSI-211 0.9 mg/m2 with cisplatin 25 mg/m2 administered intravenously daily for the first three consecutive days of a 21-day cycle. Patients were evaluated for hematological and non-hematological toxicities, and pharmacokinetic studies were performed on both agents.

Results:

The recommended phase II dose was determined to be 0.7 mg/m2 OSI-211 given with 25 mg/m2 cisplatin. Dose-limiting neutropenia was seen in two of three patients at the starting dose level. Three of 11 patients at the second (lower) dose level experienced dose-limiting thrombocytopenia; febrile neutropenia was also seen in one patient. Non-hematological toxicities were generally manageable and included fatigue, nausea and vomiting. Considerable variability was seen in both hematological toxicities and pharmacokinetics. One complete response and three partial responses were seen.

Conclusions:

The recommended phase II dose for this combination is 0.7 mg/m2 OSI-211 with 25 mg/m2 cisplatin given as an intravenous infusion on days 1, 2 and 3 of a 21-day cycle. The main toxicity was myelosuppression. Preliminary evidence of antitumor activity was seen.

Key words: liposomes, phase I, topoisomerase I


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Lurtotecan [7(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20-(S)-camptothecin dihydrochloride] is a semisynthetic analog of camptothecin, which is a derivative of the tree Camptotheca acuminata [1]. Like other camptothecin analogs, lurtotecan inhibits the ability of topoisomerase I to relax torsionally strained DNA [2].

After the demonstration of its antitumor activity in the preclinical setting, several early-phase trials were conducted with lurtotecan as a single agent. In all phase I trials, the dose-limiting toxicity (DLT) was myelosuppression, mainly neutropenia. Antitumor activity has been documented; Paz-Ares et al. [3] reported that among 44 patients with advanced solid tumors, there were three partial responses and two minor responses. Another phase I trial showed that two patients (out of 38) had partial responses [4]. Responses were observed in ovarian and small-cell lung cancers (SCLC).

A phase II trial of lurtotecan in patients with breast, colorectal and non-small-cell lung cancer (NSCLC) showed that three of 25 patients with breast cancer and two of 23 patients with NSCLC had partial responses [5]. No responses were seen among the 19 patients with colorectal cancer in this trial. In a separate trial involving 67 patients with previously treated SCLC, the overall response rate was 16% [6].

Lurtotecan has since been formulated in a low-clearance, liposomal preparation, OSI-211 (also known as NX211). Liposomal preparations of other antineoplastic agents have shown prolonged plasma exposure, improved tumor delivery and decreased toxicity [7]. In several preclinical studies, compared with lurtotecan, OSI-211 demonstrated a significant increase in plasma residence time. In mouse xenograft models, OSI-211 produced a three-fold or higher increase in therapeutic index compared with lurtotecan [2].

Eisenhauer et al. [8] have presented the results of phase I trials with three different schedules of OSI-211. The first trial (29 patients) administered OSI-211 as a 30 min infusion every 3 weeks. In the second trial OSI-211 was given on days 1, 2 and 3 (37 patients), and in the third study, OSI-211 was given on days 1 and 8 (26 patients). Eighty-six patients were evaluable for toxicity. DLTs were neutropenia and thrombocytopenia. Other toxicities included anemia, fatigue, nausea and vomiting. Partial responses were observed in patients with breast and ovarian cancers. The divided dose schedules allowed for higher dose intensity delivery, and were selected for further study in phase II trials. The recommended doses were 2.1 and 1.5 mg/m2 daily x3 (total 6.3 and 4.5 mg/m2/cycle) for the day 1, 2 and 3 schedule in minimally and heavily pretreated patients, respectively. For the day 1 and 8 schedule, the recommended dose is 2.4 mg/m2 (total 4.8 mg/m2/cycle) [8].

Goetz et al. [9] presented the results of a phase I study of OSI-211 administered weekly for 4 weeks of a 6-week cycle in patients with advanced solid tumors. Again, the major toxicity was neutropenia. The tumor response rate was not reported.

Another topoisomerase inhibitor, topotecan, has been evaluated in combination with cisplatin. Cisplatin has been used widely in the management of malignant disease for decades, and has activity in a broad range of tumor types. Unfortunately, the combination of topotecan and cisplatin caused more neutropenia than expected from either drug given alone at the same doses. Phase I trials combining cisplatin and topotecan found the combination produced additive myelosuppression, and neither drug could be given in its full single-agent dose [1012].

Preclinical studies of OSI-211 and cisplatin administered in combination in three separate tumor xenograft models (head and neck, lung, and ovarian) have been performed. These studies demonstrated increased antitumor activity in the ovarian and head and neck models compared with the single agent, but bone marrow toxicity of the combination was similar to that caused by OSI-211 alone (OSI Pharmaceuticals; data on file). The primary objective of this present trial was to determine the doses of OSI-211 and cisplatin that could be given in a daily x3 regimen and to determine whether they could be given in combination without such additive myelotoxicity. The secondary objectives were to evaluate the pharmacokinetic profile of this combination and its preliminary antitumor activity.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient selection
Patients were selected based on the following eligibility criteria: histologically or cytologically documented advanced and/or metastatic solid malignancy that was refractory to standard therapy or for which no curative therapy existed; age >18 years; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. All patients were required to have adequate bone marrow, hepatic and renal function defined as follows: an absolute neutrophil count (ANC) of ≥1.5 x 109/l, platelets ≥100 x 109/l, creatinine less than upper limit of normal (ULN) (or calculated clearance ≥60 ml/min), bilirubin ≤ULN, aspartate aminotransferase/alanine aminotransferase ≤2.5x ULN (or ≤5x ULN if documented liver metastases). Patients may have had up to one prior chemotherapy regimen (adjuvant and/or metastatic). Prior cisplatin-containing chemotherapy was allowed, providing the total dose of cisplatin was ≤300 mg/m2. A minimum of 21 days (6 weeks for nitrosoureas or mitomycin C) must have elapsed between the end of treatment and entry into the protocol, and patients must have recovered from any treatment-induced toxicities. Neuropathy and ototoxicity must have been grade ≤1 according to National Cancer Institute common toxicity criteria (NCI CTC) version 2.0. Prior radiotherapy was permitted providing that it had not encompassed >25% of the bone marrow reserve. A minimum of 4 weeks must have elapsed between completion of radiotherapy and protocol entry. Female patients of childbearing potential could not be pregnant, lactating or using inadequate birth control as defined by the protocol, and were required to have a negative pregnancy test at study entry.

Patients were excluded if they had untreated brain or meningeal metastases (patients with previously treated and stable CNS metastases were eligible). Patients with serious medical illnesses were excluded.

All patients gave written informed consent. The study was approved by local hospital and university ethics review boards and met institutional and federal guidelines.

Trial design
This was a phase I, open-label, non-randomized, dose-finding study of the combination of cisplatin and OSI-211 given as intravenous infusions on days 1, 2 and 3 of an 3 week cycle. The schedule of three consecutive days was selected because the phase I trial of OSI-211 given in this schedule was promising in terms of antitumor activity and, at least in some clinical settings such as SCLC, cisplatin may be given in a daily x3 dosing schedule. The starting dose of OSI-211 was 0.9 mg/m2 (<50% of the recommended single-agent dose for minimally pretreated patients). The dose of cisplatin was fixed in all dose levels at 25 mg/m2, which is the standard dose used in daily x3 regimens.

The study, conducted under the auspices of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), accrued patients from three participating centers: the Hamilton Regional Cancer Centre, the Princess Margaret Hospital/University Health Network and the British Columbia Cancer Agency–Vancouver Center Hospital. All patients were registered with the NCIC CTG central office and assigned to a dose level. Data monitoring was performed by NCIC CTG and OSI Pharmaceuticals.

Treatment plan
Pretreatment evaluation included history, physical examination, complete blood count, chemistry, urinalysis, ECG, chest X-ray and radiological assessment, with other scans/X-rays as necessary to document disease. A pregnancy test was performed in women of childbearing potential. A complete toxicity evaluation was performed to document residual toxicity from previous therapy and baseline symptoms.

Patients were reviewed every 3 weeks by one of the investigators to assess symptoms and signs. A complete blood count was performed on day 1 and twice weekly during cycle 1, and on day 1 and weekly during subsequent cycles. Biochemistry was drawn on day 1 and weekly during cycle 1, and then on day 1 of subsequent cycles. Formal tumor measurements were performed after every two cycles of treatment. Toxic effects were monitored continuously according to the NCI CTC version 2. No routine hematopoetic growth factors were given.

OSI-211 was administered by intravenous infusion (over 30 min) on an outpatient basis on days 1, 2 and 3 of a 21-day cycle. Patients received cisplatin 25 mg/m2/day intravenously over 1 h on days 1, 2 and 3 of the cycle immediately preceding the OSI-211 infusion. All patients were premedicated with dexamethasone 10 mg by mouth or intravenously, and ondansetron 8 mg by mouth before each treatment. Patients routinely received 500 ml normal saline as prehydration. No other routine prophylactic premedications or co-medications were administered.

Treatment was continued until the patient developed disease progression or unacceptable toxicity, or withdrew his or her consent.

Dose escalation and dose modifications
Initially, three patients were to be enrolled at each dose level. If no patients exhibited DLT at a given level, escalation would proceed to the next dose level, according to a modified Fibonacci schedule. If one of three patients had a DLT, then three additional patients were to be enrolled in that cohort. If two or more patients had a DLT, that dose was to be declared the maximum tolerated dose (MTD), and the next lower dose level expanded as the recommended phase II dose. The dose of OSI-211 was not to be escalated in individual patients.

Response criteria
Patients were considered assessable for response if they had received at least one cycle of therapy and had their disease re-evaluated. Measurable lesions were defined as those that could be accurately measured in at least one dimension as ≥20 mm with conventional techniques [physical exam, computed tomography (CT) scan, X-ray, magnetic resonance imaging] or as ≥10 mm with spiral CT scan. All measurable lesions were evaluated at least every two cycles using the RECIST criteria [13]. A complete response was defined as the disappearance of all clinical and radiological evidence of tumor. A partial response was a reduction of at least 30% in the sum of the longest dimension of target lesions. Progressive disease was defined as a 20% or more increase in the sum of the longest dimensions of measured lesions, or the appearance of new lesions.

Pharmacokinetic analysis
The pharmacokinetics of OSI-211 and cisplatin were studied on days 1–5 of the first cycle of treatment only. On days 1 and 3, blood samples were collected before drug administration, and thereafter at 60 min (at the end of the cisplatin infusion and prior to the beginning of the OSI-211 infusion), 90, 120, 150, 180 and 210 min, and at 5 and 8 h after the end of the OSI-211 infusion. One sample was collected on day 2 prior to initiating the day 2 OSI-211 infusion. One sample was taken on day 4 and another on day 5, 23.5 and 46.5 h after the end of the day 3 OSI-211 administration. Plasma samples were analyzed by reverse-phase high-pressure liquid chromatography with fluorescence detection. The total concentration of OSI-211 is reported (lactone and carboxylate forms of OSI-211 were not determined independently).

The maximum plasma concentration (Cmax), area under the curve from time zero to infinity (AUC0–{infty}), plasma clearance, volume of distribution (Vd) of the central compartment at steady state and elimination half-life were determined.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
The patient characteristics are detailed in Table 1. Fourteen patients were enrolled onto the study between March 2000 and November 2001. All were evaluable for hematological and non-hematological toxicity. Eleven were evaluable for response. Of the three patients not evaluable, two did not have repeat radiology to re-assess disease (one of these patients was removed from study due to symptomatic progression after one cycle of treatment; the other was removed due to elevated creatinine). The third non-evaluable patient had non-measurable disease.


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics (n = 14)
 
Nine patients were female and five were male. All patients had ECOG status <2 at the time of enrollment. Six of the patients had no prior chemotherapy and eight had one previous chemotherapy regimen. Five patients had a diagnosis of ovarian cancer, four had head and neck cancer, and one each had cervical, renal, peritoneal, thyroid and unknown primary carcinoma.

Drug delivery
At the first dose level (0.9 mg/m2/day OSI-211 and 25 mg/m2 cisplatin), dose-limiting myelosuppression was encountered in two of the three patients entered; thus, further enrolment of patients was undertaken at the –1 dose level of OSI-211, 0.7 mg/m2 plus cisplatin 25 mg/m2, the dose level that is recommended for further evaluation. A total of 61 courses of chemotherapy were delivered at the two dose levels. Table 2 outlines the total number of cycles of chemotherapy at each dose level.


View this table:
[in this window]
[in a new window]
 
Table 2. Dose levels, number of patients and number of cycles
 
The number of cycles given at dose level 1 ranged from two to five (median five cycles). The number of cycles given at dose level –1 ranged from one to six (median six cycles).

Toxicity
Hematological toxicity. Table 3 displays the median nadir of the ANC, hemoglobin and platelets by cohort. As described above, at the starting dose of 0.9 mg/m2 OSI-211 with 25 mg/m2 cisplatin, two of three patients experience DLT. One patient was neutropenic (grade 4) for >7 days. A second patient developed febrile neutropenia on day 19 of treatment. This patient was admitted to hospital for treatment with intravenous antibiotics, and subsequently recovered.


View this table:
[in this window]
[in a new window]
 
Table 3. Hematological toxicity (worst ever by starting dose)
 
Because the first dose level was thus declared the MTD, a reduced dose level of 0.7 mg/m2 OSI-211 was opened. Initially, four patients were registered to this dose level, and two of these patients required cycle 2 delays due to neutropenia. As a result, four additional patients were enrolled at this level to obtain a broader picture of the bone marrow effects. When two of these four patients experienced DLTs in the form of thrombocytopenia and febrile neutropenia, three further patients were enrolled. One of these patients experienced grade 3 thrombocytopenia. Therefore, in total, three of 11 patients at this new level had a DLT. However, because wide inter-patient variability was observed (with some patients having little or no toxicity), this dose was declared the recommended level for phase II study.

Non-hematological toxicity. Non-hematological effects occurring on the study are detailed in Table 4. The most common non-hematological effects were fatigue, nausea and vomiting, and none was dose limiting. One 64-year-old patient with peritoneal cancer was admitted to hospital with myocardial infarction on day 9 of her fifth course of therapy. Following appropriate in hospital care she recovered and was discharged. Owing to the temporal sequence of the event with treatment, a relationship to study therapy could not be excluded. She was therefore removed from the study.


View this table:
[in this window]
[in a new window]
 
Table 4. Non-hematological toxicity: worst grade by patient, any relationship to therapy
 
In patients with normal baseline biochemistry, some elevations in liver enzymes, primarily grade 1, were seen. However, two patients were removed from study due to elevations in creatinine after one and two cycles of therapy were given. Overall, five patients had creatinine elevations (three patients with grade 1; two patients with grade 2), and, because of the known effects of cisplatin on renal function, these elevations are likely related to the combination protocol therapy.

Pharmacokinetics
Pharmacokinetic results (including AUC, Cmax, Vd, clearance and half-life) are reported in Table 5. Pharmacokinetic evaluation was performed in 14 patients. OSI-211 pharmacokinetics showed results that were similar to those observed previously in single-agent trials at the dose levels given in this study. There was little intra-patient variability, but marked inter-patient variability. As was the case in the single-agent phase I studies, the variability of toxicity (in particular myelosuppression) could not be explained by the variability in pharmacological behavior of the drug.


View this table:
[in this window]
[in a new window]
 
Table 5. Pharmacokinetics for cisplatin and OSI-211
 
A statistically significant rise in the AUC of cisplatin between days 1 and 3 was noted in the group receiving 0.7 mg/m2 OSI-211 (P = 0.0090, paired t-test). Such elevations in AUC and Cmax have been noted when platinum is administered as monotherapy. Therefore, it is unlikely that the increase is a result of co-administration with OSI-211 [14].

Antitumor response
Eleven patients were evaluable for response. One patient (with anaplastic thyroid cancer) had a complete response. The response was sustained for the duration of treatment (six cycles) and the patient relapsed 6 months after discontinuation. Three had partial responses (ovarian, peritoneal, and head and neck). The median duration for partial response was 4.7 months (range 3.9–14.1). Six patients had stable disease; the median duration of stable disease was 6.9 months (range 2.4–11.2). One patient had progressive disease.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
OSI-211, a liposomal preparation of the camptothecin analog lurtotecan, has shown antitumor activity in phase II evaluation [15]. Cisplatin is a widely used antineoplastic agent with activity in a broad range of tumor types. Because the combination of camptothecin and platinum is logical given the spectrum of activity of both these classes of agents, we carried out this phase I trial to determine the MTD and toxicity profile of OSI-211 and cisplatin.

Unfortunately, significant myelotoxicity was seen at the starting dose in the first cohort, and therefore subsequent patients were enrolled at a lower dose level. The results of this trial are similar to those documented in previous phase I trials of cisplatin combined with topotecan [1012], indicating the preclinical toxicology that suggested there might not be additive myelosuppression when OSI-211 was given in combination with cisplatin were misleading in this regard.

Although myelotoxicity was again seen in this second cohort given reduced doses of OSI-211, there was significant inter-patient variability in the toxicities seen. As three of 11 patients had a DLT at the second (lower) level, the recommended dose for phase II studies is 0.7 mg/m2 OSI-211 and 25 mg/m2 cisplatin for three consecutive days in a 21-day cycle.

The pharmacokinetic evaluation of these patients also showed interpatient variability in OSI-211 AUC, Cmax, Vd and clearance. The variability of toxicity (in particular myelosuppression) could not be explained by the variability in pharmacological behaviour of the drug.

Non-hematological adverse effects were manageable, with no DLTs seen. The most common non-hematological toxicities were gastrointestinal.

The study combination did show antitumor activity, with one complete and three partial responses seen. It should be noted, however, that these responses occurred in patients with malignancies that are known to be responsive to platinum analogs; thus it is unclear whether the activity seen was related to the combination being given, or simply administration of the platinum component.

Since this trial was initiated, others have shown that the preferred schedule for OSI-211 administration is the daily x3 regimen we employed in this study [15]. Thus, should this agent be pursued further in combination with cisplatin, the daily x3 schedule we have studied may merit further evaluation in solid tumors, where OSI-211 has shown activity.


    Acknowledgements
 
This study was supported by grants from the National Cancer Institute of Canada and OSI Pharmaceuticals.


    FOOTNOTES
 
* Correspondence to: Dr E. Eisenhauer, NCIC Clinical Trials Group, Cancer Research Institute, 10 Stuart Street, Queen’s University, Kingston, Ontario, Canada K7L 3N6. Tel: +1-613-533-6430; Fax: +1-905-575-6326; E-mail: eeisenhauer{at}ctg.queensu.ca Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
1. Kehrer DFS, Bos AM, Verweij J et al. Phase I and pharmacologic study of liposomal lurtotecan, NX211: urinary excretion predicts hematologic toxicity. J Clin Oncol 2002; 20: 1222–1231.[Abstract/Free Full Text]

2. Emerson DL, Bendele R, Brown E et al. Antitumor efficacy, pharmacokinetics, and biodistribution of NX211: a low-clearance liposomal formulation of lurtotecan. Clin Cancer Res 2000; 6: 2903–2912.[Abstract/Free Full Text]

3. Paz-Ares L, Kunka R, De Maria D et al. A phase I and pharmacokinetic study of the new topoisomerase inhibitor G1147211 given as a 72-h continuous infusion. Br J Cancer 1998; 78: 1329–1336.[ISI][Medline]

4. Stevenson JP, DeMaria D, Sludden J et al. Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day infusion. Ann Oncol 1999; 10: 339–344.[Abstract]

5. Gamucci T, Paridaens R, Heinrich B et al. Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: an EORTC-ECSG phase II clinical study. Ann Oncol 2000; 11: 793–797.[Abstract]

6. Sessa C, Wanders J, Roelvink M et al. Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: a study of the EORTC Early Clinical Studies Group (ECSG). Ann Oncol 2000; 11: 207–210.[Abstract]

7. Mayer LD, Cullis PR, Bally MB. Designing therapeutically optimized liposomal anti-cancer delivery systems: lessons from conventional liposomes. In Lassic D, Papahadjopoulos D (eds): Medical Applications of Liposomes. Amsterdam, The Netherlands: Elsevier Press 1998; 231–256.

8. Eisenhauer EA, Verweij J, Rothenberg ML et al. Phase I evaluation of liposomal topoisomerase I inhibitor, NX211, administered by three schedules to patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001; 20 (Abstr 409).

9. Goetz AD, Hammond LA, Hao D et al. A Phase I and pharmacokinetic study of NX211 (liposomal lurtotecan) administered weekly x 4 every 6 weeks in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2002; 21 (Abstr 388).

10. Miller AA, Hargis JB, Lilenbaum RC et al. Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a Cancer and Leukemia Group B study. J Clin Oncol 1994; 12: 2743–2750.[Abstract]

11. Lilenbaum RC, Miller AA, Batist G et al. Phase I and pharmacologic study of continuous infusion topotecan in combination with cisplatin in patients with advanced cancer. J Clin Oncol 1998; 16: 3302–3309.[Abstract]

12. Raymond E, Burris HA, Rowinsky EK et al. Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non-small cell lung carcinoma. Ann Oncol 1997; 8: 1003–1008.[Abstract]

13. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumours. European Organization for Research and Treatment of Cancer, National Cancer Institute of United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.[Abstract/Free Full Text]

14. Gamelin E, Allain P, Maillart P et al. Long term pharmacokinetic behavior of platinum after cisplatin administration. Cancer Chemother Pharmacol 1995; 37: 97–102.[CrossRef][ISI][Medline]

15. Calvert AH, Grimshaw R, Poole C et al. Randomized phase II trial of two intravenous schedules of the liposomal topoisomerase I inhibitor, NX211, in women with relapsed epithelial ovarian cancer (OVCA): an NCIC CTG study. Proc Am Soc Clin Oncol 2002; 21 (Abstr 830).





This Article
Abstract
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by MacKenzie, M. J.
Articles by Eisenhauer, E.
PubMed
PubMed Citation
Articles by MacKenzie, M. J.
Articles by Eisenhauer, E.