Surgical adjuvant therapy of rectal carcinoma: a controlled evaluation of leucovorin, 5-fluorouracil and radiation therapy with or without interferon-{alpha}2b

C. Gennatas1,+, C. Dardoufas1, D. Mouratidou2, N. Tsavaris3, A. Pouli1, G. Androulakis4, M. Philippakis5, D. Voros1, T. Batalis5, S. Besbeas6, G. Hatzistylianos5, J. Katsos7, V. Komporozos8, N. Legakis4, H. Mallas1, G. Peros5, A. Photopoulos1, C. Pisiotis9, G. Polymeneas1, G. Retalis1, L. Samanidis1, V. Smyrniotis1, A. Stamatiadis5, J. Vasiliou1, H. Andreadis2 and J. Papadimitriou1

1 Second Department of Surgery, Areteion Hospital, University of Athens, Athens; 2 Third Department of Medical Oncology, Theagenion Cancer Hospital, Salonika; 3 Department of Medicine, Laikon Hospital, University of Athens, Athens; 4 Fourth Department of Surgery, Nikaia General Hospital, University of Athens, Athens; 5 Department of Surgery, Evgenidion Hospital, Athens; 6 Department of Surgery, Agios Savas Cancer Hospital, Athens; 7 Department of Gastrointestinal Medicine, Theagenion Cancer Hospital, Salonika; 8 Department of Surgery, Red Cross Hospital, Athens; 9 Department of Surgery, Evangelismos Hospital, Athens, Greece

Received 8 July 2002; revised 1 October 2002; accepted 22 October 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV) and radiation therapy (RT) could be improved by the addition of interferon-{alpha}2b (IFN-{alpha}) in patients who have had a ‘curative’ resection, for rectal adenocarcinoma (Dukes’ B2/C; T3 N0, T4 N0, N1–3).

Patients and methods:

A total of 207 eligible patients with a performance status of 0 or 1 were randomized postoperatively between days 21 and 70 to one of the two treatment groups: group A, LV 20 mg/m2 i.v. bolus and 5-FU 425 mg/m2 i.v. days 1–5 and 29–33, LV 20 mg/m2 and 5-FU 400 mg/m2 days 57–60 and 85–88, LV 20 mg/m2 and 5-FU 380 mg/m2 days 1–5 and 29–33 with the second day 1 occurring 28 days after the completion of RT (45 Gy); group B, LV, 5-FU and RT as in group A, and IFN-{alpha} 5 x 106 IU s.c. three times during each week chemotherapy is given.

Results:

104 patients were randomized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups. Toxicity was also the same, except for the flu-like syndrome associated with the IFN-{alpha} administration.

Conclusions:

There was no difference in efficacy between the two combinations. Toxicity was greater with the LV + 5-FU + IFN-{alpha} regimen because of the flu-like syndrome.

Key words: adjuvant chemotherapy, adjuvant radiotherapy, randomized controlled trial, rectal neoplasm


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Surgery remains the primary treatment for localized carcinoma of the rectum. However, it is followed by local and/or distant relapses in ~50% of patients, equally divided between those treated with surgery alone for stage II and III rectal cancer [1]. The risk of tumor relapse correlates with both the degree of tumor penetration through the rectal wall and the extent of lymph node metastases. There is definite indication for adjuvant therapy in this group of patients. A Gastrointestinal Tumor Study Group trial of 202 patients, initiated in 1975, revealed a significant survival advantage for patients treated with surgery followed by both adjuvant chemotherapy [5-fluorouracil (5-FU) and semustine] and radiation therapy (RT), compared with those who received surgery alone [2]. A North Central Cancer Treatment Group trial of 204 patients, initiated in 1980, documented a statistically significant improvement in 5-year rates of tumor recurrence and survival for patients who received both RT and chemotherapy (5-FU and semustine) [3]. These two trials served as the basis for recommendations by the National Institutes of Health Consensus Development Conference in 1990 for combined chemotherapy and RT as postoperative adjuvant therapy in clinical practice for patients with stage II and III rectal cancer [1, 4].

Interferon-{alpha}2b (IFN-{alpha}) has been shown to enhance the cytotoxic activity of 5-FU in human cancer cell-lines. The mechanism of this enhancement is probably multifactorial, as several mechanisms have been implicated. Studies on cultured colon adenocarcinoma cells and in murine models supported the use of an IFN-{alpha} and 5-FU combination in patients with colon cancer [57].

The aim of this study was to compare the combination of 5-FU, leucovorin (LV) and RT with the combination of 5-FU, LV, IFN-{alpha} and RT in patients who have had a ‘curative’ resection for rectal adenocarcinoma (Dukes’ B2 and C; T3 N0, T4 N0 or N1–3), to determine whether the efficacy of the 5-FU–LV combination with RT can be improved by the addition of IFN-{alpha}. A comparison of the toxicity of the two regimens was carried out at the same time.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Patients were eligible for this study if they had histological proof of adenocarcinoma of the rectum and if a potentially curative resection of the primary tumor and regional lymph nodes had been performed with no evidence of either gross or microscopic residual disease. The tumor had to have a pathological indicator of a poor prognosis, either extension of the primary tumor through the bowel wall or positive lymph nodes without evidence of distant metastases (T3/4 or N1–3, and M0). A tumor was considered rectal if the gross inferior margin of the primary tumor was located below the peritoneal reflection. All patients had to be older than 18 years of age with a performance status (PS) of 0 or 1. Patients were randomized between 21 and 70 days postoperatively. Patients could not have received prior RT to the pelvis or previous chemotherapy and must have recovered from the acute effects of surgery. There could be no other serious medical illness that would limit the ability of the patient to receive protocol therapy. The scientific committees of the participating hospitals approved the study protocol and all patients signed an informed consent before randomization.

All patients received an initial two cycles of chemotherapy, followed by pelvic RT accompanied by two cycles of chemotherapy, and two more cycles of chemotherapy after the completion of RT.

Chemotherapy regimens
Group A. First two cycles, LV 20 mg/m2/day i.v. bolus and 5-FU 425 mg/m2/day i.v. for 5 consecutive days on days 1–5 and 29–33; two cycles administered with RT, LV 20 mg/m2/day and 5-FU 400 mg/m2/day on days 57–60 and 85–88; final two cycles, LV 20 mg/m2/day and 5-FU 380 mg/m2/day on days 1–5 and 29–33 starting 28 days after the completion of RT.

Group B. LV and 5-FU as in group A. IFN-{alpha} 5 x 106 IU s.c. three times during each week chemotherapy was given.

Radiation therapy
All patients received pelvic RT with concurrent chemotherapy with LV, 5-FU ± IFN-{alpha}. Field arrangement depended on surgical and pathological frindings; however, the following generalizations were used. The width of the anterior-posterior: posterior-anterior (AP:PA) ports covered the pelvic outlet with a margin around the desired internal and external iliac nodes. Lateral margins extending 1–1.5 cm beyond the widest point of the bony pelvis were considered sufficient. The superior margins were at least 1.5 cm above the level of the sacral promontory. The inferior margin included the obturator foramina. Treatments were given with 6 MeV linear accelerators. The adjuvant dose levels of radiation required to achieve a high incidence of local control are close to the radiation tolerance of the small bowel. Therefore, great care was taken to localize tumor volumes and decrease the amount of small intestine within the irradiation field [8, 9]. The planning system was connected to a computed tomography (CT) scan, and the treatment planning was based on the CT findings. A 4-field technique was used to minimize the amount of small bowel exposed to treatment. The use of individualized blocks allowed a larger amount of small bowel to be shielded from the radiation fields. Patients were treated in a prone position with a full bladder in order to push the small bowel as up and out from the treatment field as possible. All fields were treated daily, resulting in a lower integral dose and more homogeneous dose distribution. The whole pelvis was treated at 1.8 Gy per fraction to a total dose of 45 Gy. After the completion of the pelvis treatment, a boost dose of 5.4 Gy was given to the tumor bed to a modal dose of 50.4 Gy.

Follow-up
Patients were followed-up at 6-month intervals after the completion of therapy for 5 years, then yearly. At follow-up evaluation, patients had a history and physical examination, complete blood count, liver chemistries, carcinoembryonic antigen test, CA 19-9 assay, chest X-ray and CT scan of the abdomen. A colonoscopy was recommended at 6, 18, 30 and 54 months after surgery or when indicated.

Statistical analysis
An accrual of 103 patients in each treatment arm was planned for this study. This number was considered sufficient to test the difference between the two groups, whilst allowing the completion of the study in a reasonable period of time considering the accrual potentials of the participating institutions. A total of 207 patients were finally randomized from nine participating centers. One hundred and four patients (50.2%) received LV, 5-FU and RT, while the remaining 103 (49.8%) received LV, 5-FU, IFN-{alpha} and RT. All of them were considered evaluable and analyzed.

All individual data were listed. All parameters were presented descriptively. Tables of descriptive statistical parameters (number of non-missing values, mean, standard deviation, median, range) and/or contingency tables (number of non-missing values, percentage) were constructed in each case. The baseline comparability of the treatment groups was explored with respect to demographic data and other patients’ characteristics. Patients’ age was compared with one-way analysis of variance (ANOVA). Sex, PS and type of resection were evaluated using Pearson’s {chi}2 test. Nodal involvement and T stage were analyzed using Wilcoxon rank-sum tests. Estimations of the survivor function were derived from the Kaplan–Meier estimates. Differences between groups of patients were tested by both the log-rank and Wilcoxon statistic. If the estimated survivor functions did not cross, the assumption of proportional hazard was justified and the log-rank test was more appropriate. Alternatively, the Wilcoxon test was more appropriate than the log-rank test for comparing the two survivor functions. The Cox regression model (proportional hazard model) was used to determine which combinations of potential explanatory variables affected the form of hazard function. All P values were not adjusted and were derived from two-sided tests. The level of significance was fixed with {alpha} at 5%. A P value of <=0.05 was taken to indicate statistical significance. The statistical analysis was carried out with the software product SAS (SAS Institute, Cary, NC, USA) version 8.1.

Patient eligibility, site of relapse, cause of death and toxicity were reviewed for all patients by the principal investigator. There were no protocol violations. The study was activated in December 1990 and the last patient was registered in June 1999.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 207 patients have been randomized, 104 into group A and 103 into group B. Characteristics of these patients are displayed according to study arm assignment in Table 1. No statistically significant differences were detected between treatment groups according to patients’ age [ANOVA: F = 0.022, degrees of freedom (d.f.) 1, P = 0.883], sex (Pearson: {chi}2 = 0.058, d.f. 1, P = 0.810) or disease stage (Wilcoxon = 10751.5, P = 0.9091).


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 
Concerning PS, nodal involvement and type of resection, subject distribution was similar in the two treatment groups. No statistically significant differences were detected for PS ({chi}2 = 0.116, d.f. 1, P = 0.733), type of resection ({chi}2 = 0.001, d.f. 1, P = 0.972) or nodal involvement (Wilcoxon = 10750.5, P = 0.922).

Disease-free survival was measured from study entry until initial tumor relapse (local recurrence or distant). Overall survival was measured from study entry until death. There were 85 (41.1%) recurrences or metastases within the follow-up period: 44 (42.3%) from group A and 41 (39.8%) from group B. The difference between the two groups was not statistically significant ({chi}2 = 0.134, d.f. 1, P = 0.715). In addition, 55 (26.6%) subjects died defore the end of the study: 29 (27.9%) in group A and 26 (25.2%) in group B. Again, the difference was not statistically significant ({chi}2 = 0.185, d.f. 1, P = 0.667).

Analysis of the disease-free survival shows no significant difference between the treatment groups (Figure 1). Analysis of the overall survival gave similar results to the disease-free survival (Figure 2). In fact, survival curves produced for patients allocated to treatments A and B could not be distinguished.



View larger version (22K):
[in this window]
[in a new window]
 
Figure 1. Kaplan–Meier estimate of the disease-free survival functions for patients with rectal adenocarcinoma who received treatment A (continuous line) or treatment B (dashed line). cens, censored data (P = 0.82).

 


View larger version (22K):
[in this window]
[in a new window]
 
Figure 2. Kaplan–Meier estimate of the overall survival functions for patients with rectal adenocarcinoma who received treatment A (continuous line) or treatment B (dashed line). cens, censored data (P = 0.73).

 
Analysis of recurrence- or metastasis-free periods, by applying a Cox proportional hazard model, revealed that the hazard of death was greater in subjects with T4 stage disease. More precisely, the hazard of death at any given time for subjects with stage T4 disease was >2.77 (e1.019) times that for someone with stage T0–2. Similarly, the hazard ratio for an individual with more than three involved nodes was e2.294 = 9.913, while it was e1.383 = 3.988 for an individual with one to three involved nodes. Finally, it was found that the greater the age of a patient, the greater the hazard of death at any given time.

Toxicity
All patients were assessable for toxicity. The ECOG toxicity criteria were used. Toxic reactions are presented in Table 2. There were no toxicity-associated deaths. There was no difference in toxicity between the two groups with the exception of the flu-like syndrome. The flu-like syndrome included fever, arthralgia, myalgia, abdominal pain, chills, rigor and fatigue, and was universal in IFN-{alpha} treated patients. No case of significant liver toxicity was recorded. In no case was treatment discontinued because of toxicity. In two patients from each group, 5-FU was reduced because of leucopenia. In 18 patients, 10 from group A and eight from group B, 5-FU was reduced because of diarrhea. There was no statistically significant difference between the two groups with the exception of the flu-like syndrome (P <0.001).


View this table:
[in this window]
[in a new window]
 
Table 2. Incidence of grades 2, 3 and 4 toxicity by treatment arm and type of toxicity
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
It is well known that for more than four decades 5-FU-based chemotherapy regimens have been the mainstay of treatment for patients with locally advanced or metastatic carcinoma of the colon and rectum. While none of the 5-FU regimens has been universally accepted as superior in terms of efficacy, the bolus 5-FU/LV Mayo Clinic regimen is used in many centers around the world. It has been the ‘gold standard’ in the management of metastatic carcinoma of the colon and rectum for several years and so it was decided to use it as the first arm of this study.

Interferons-{alpha}, ß and {gamma} enhance the activity of 5-FU in vitro and in vivo [57, 10]. Preclinical research concerning the interaction of 5-FU and IFN-{alpha} has been summarized by Grem et al. [11]. Although the mechanism by which IFNs modulate 5-FU activity is not completely elucidated, several clinical trials have evaluated the 5-FU + IFN-{alpha} combination or the double modulation (LV and IFN-{alpha}) of 5-FU with encouraging results [1224]. We have evaluated the 5-FU + IFN-{alpha} combination in a study of 25 patients with advanced colon carcinoma with satisfactory results and acceptable toxicity [25]. Therefore, it was considered worthwhile evaluating this combination at an early stage of the disease with a low tumor burden. At this stage the immunomodulatory properties of IFN-{alpha} could be helpful.

In 1994, Frasci et al. reported the results of a study comparing 5-FU + IFN-{alpha}2b with 5-FU alone in patients with Dukes’ C colorectal cancer [26]. In their study, which had the limitation of using historic controls, the combination seemed to improve prognosis. Both 5-year relapse-free survival and cause-specific survival were significantly better in the patients receiving the combined treatment. There was no significant toxicity and the addition of IFN-{alpha} only slightly impaired tolerance to treatment [26]. Data from the National Surgical Adjuvant Breast and Bowel Project protocol C-05, which included 2176 patients with carcinoma of the colon, did not reveal any benefit from the addition of IFN-{alpha} to 5-FU + LV [27]. The addition of IFN-{alpha} increased the overall toxicity and adversely affected patient compliance. In this study, the combination of 5-FU + IFN-{alpha} did not increase hematological toxicity and did not affect patient compliance. It was associated with increased toxicity because of the flu-like syndrome, which was universal in IFN-{alpha} treated patients. We have previously found the same toxicity results with 5-FU + IFN-{alpha} in the adjuvant treatment of carcinoma of the colon [28].

We conclude that patients with resected stage II or III rectal cancer should be offered adjuvant therapy with a combination of RT and chemotherapy [29]. Chemotherapy should include 5-FU. Intravenous infusion of 5-FU is more effective than bolus injection [29]. Long-term i.v. infusion presents several problems for the patient, as well as the medical and nursing staff, so it is reasonable to include the novel fluoropyrimidine capecitabine in future studies. Capecitabine is an oral fluoropyrimidine derivative that delivers 5-FU to target cells with predictable kinetics. Oral administration enables sustained exposure to 5-FU and avoids the technical barriers of i.v. administration [30]. There is no evidence to support the addition of IFN-{alpha} in this indication.


    Footnotes
 
+ Correspondence to: Dr C. Gennatas, University of Athens, 5 Arnis Street, 11528 Athens, Greece. Tel: +30-210-724-4758; Fax: +30-210-620-7349; E-mail: gennatas{at}compulink.gr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. O’Connell M. Surgical adjuvant therapy of rectal cancer: chemotherapy considerations. 34th Annual ASCO Meeting. ASCO Educational Book 1998; 419–424.

2. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985; 312: 1465–1472.[Abstract]

3. Krook JE, Moertel CG, Gunderson L et al. Effective adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324: 709–715.[Abstract]

4. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264: 1444–1450.[CrossRef][ISI][Medline]

5. Wadler S, Schwartz EL, Goldman M et al. Fluorouracil and recombinant {alpha}-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1769–1775.[Abstract]

6. Wadler S, Schartz EL. Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 1990; 50: 3473–3786.[Abstract]

7. Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin Oncol 1984; 2: 336–352.[Abstract]

8. Gunderson LL. Colorectal cancer. In Perez C, Brady L (eds): Principles of Radiation Oncology. Philadelphia, PA: J.B. Lippincott Company 1987.

9. Gunderson LL, Russell AH, Llewllyn HJ et al. Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 1985; 11: 1379–1393.[ISI][Medline]

10. Houghton JA, Cheshire PJ, Morton CL, Stewart CF. Potentiation of 5-fluorouracil–leucovorin activity by {alpha}2a-interferon in colon adenocarcinoma xenografts. Clin Cancer Res 1995; 1: 33–40.[Abstract]

11. Grem JL, van Groeningen CJ, Ismail AA et al. The role of interferon-{alpha} as a modulator of fluorouracil and leucovorin. Eur J Cancer 1995; 31A: 1316–1320.[CrossRef]

12. Pazdur R, Ajani JA, Patt YZ et al. Phase II evaluation of recombinant {alpha}-2a-interferon and continuous infusion fluorouracil in previously untreated metastatic colorectal adenocarcinoma. Cancer 1993; 71: 1214–1218.[ISI][Medline]

13. Dufour P, Husseini F, Dreyfus B et al. 5-Fluorouarcil versus 5-fluorouracil plus {alpha}-interferon as treatment of metastatic colorectal carcinoma. A randomized study. Ann Oncol 1996; 7: 575–579.[Abstract]

14. John WJ, Neefe JR, MacDonald JS et al. 5-Fluorouracil and interferon-{alpha}2a in advanced colorectal carcinoma. Results of two treatment schedules. Cancer 1993; 72: 3191–3195.[ISI][Medline]

15. Wadler S, Lembersky B, Atkins M et al. Phase II trial of fluorouracil and recombinant interferon {alpha}-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1991; 9: 1806–1810.[Abstract]

16. Huberman M, McClay E, Atkins M et al. Phase II trial of 5-fluorouracil (5-FU) and recombinant {alpha}-2a interferon in advanced colorectal cancer. Proc Am Soc Clin Oncol 1991; 10: 153 (Abstr 478).

17. Kemeny N, Younes A, Seiter K. Interferon {alpha}-2a and 5-fluorouracil for advanced colorectal carcinoma. Assessment of activity and toxicity. Cancer 1990; 66: 2470–2475.[ISI][Medline]

18. Douillard JY, Leborgne J, Danielou JY et al. Phase II trial of 5-fluorouracil and recombinant {alpha}-interferon in metastatic previously untreated colorectal cancer. Proc Am Soc Clin Oncol 1991; 10: 139 (Abstr 422).

19. Hansen RM, Ritch PS, Libnoch JA, Anderson T. Continuous 5-fluorouracil infusion and {alpha}-interferon in advanced cancers: a report of initial treatment results. Am J Med Sci 1991; 301: 246–249.[ISI][Medline]

20. Raderer M, Scheithauer W. Treatment of advanced colorectal cancer with 5-fluorouracil and interferon-{alpha}: an overview of clinical trials. Eur J Cancer 1995; 31A: 1002–1008.[CrossRef]

21. Hill M, Norman A, Cunningham D et al. Royal Marsden phase III trial of fluorouracil with or without interferon {alpha}-2b in advanced colorectal cancer. J Clin Oncol 1995; 13: 1297–1302.[Abstract]

22. Hill M, Norman A, Cunningham D et al. Impact of protracted venous infusion fluorouracil with or without interferon {alpha}-2b on tumour response, survival and quality of life in advanced colorectal cancer. J Clin Oncol 1995; 13: 2317–2323.[Abstract]

23. Phase III randomized study of two fluorouracil combinations with either interferon {alpha}-2a or leucovorin for advanced colorectal cancer. Corfu-A Study Group. J Clin Oncol 1995; 13: 921–928.[Abstract]

24. Ragnhammar P, Blomgren H, Edler D et al. Different dose regimens of 5-fluorouracil and interferon-{alpha} in patients with metastatic colorectal carcinoma. Eur J Cancer 1995; 31A: 315–320.[CrossRef]

25. Gennatas C, Polymeneas G, Samanidis L et al. Interferon-{alpha} and 5-fluorouracil combination in patients with advanced colon carcinoma. Hellenic J Gastoenterology 1991; 4 (Suppl): 196 (Abstr).

26. Frasci G, Leone F, Monaco M et al. 5-Fluorouracil–interferon-{alpha} 2b adjuvant treatment of Dukes’ C colorectal cancer. Dis Colon Rectum 1994; 37: 643–650.[ISI][Medline]

27. Wolmark N, Bryant J, Smith R et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon {alpha}-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 1998; 90: 1810–1816.[Abstract/Free Full Text]

28. Gennatas C, Mouratidou D, Androulakis G et al. Adjuvant systemic therapy protocol for Dukes’ B2 and C resectable colon carcinoma. Tumori 2002; 88: 32–36.[ISI][Medline]

29. Figueredo A, Germond C, Taylor B et al. Post-operative adjuvant radiotherapy or chemotherapy for resected stage II or III rectal cancer. Curr Oncol 2000; 7: 37–51.

30. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001; 19: 2282–2292.[Abstract/Free Full Text]





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
Disclaimer
Request Permissions
Google Scholar
Articles by Gennatas, C.
Articles by Papadimitriou, J.
PubMed
PubMed Citation
Articles by Gennatas, C.
Articles by Papadimitriou, J.