Clinical Trials and NCI Resources for Cancer in HIV-Positive Patients

February 1, 2002

The association between HIV infection and the development of cancer was noted early in the acquired immunodeficiency syndrome (AIDS) epidemic. The AIDS-defining malignancies are Kaposi’s sarcoma, intermediate- or high-grade B-cell non-Hodgkin’s lymphoma (NHL), and cervical cancer. All of these cancers feature specific infectious agents in their etiology. These agents are human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus, or HHV-8/KSHV (implicated in Kaposi’s sarcoma), Epstein-Barr virus, or EBV (in primary central nervous system lymphoma and a subset of systemic B-cell NHL) and human papillomavirus, or HPV (in cervical cancer).[1]

The association between HIV infection and the development ofcancer was noted early in the acquired immunodeficiency syndrome (AIDS)epidemic. The AIDS-defining malignancies are Kaposi’s sarcoma, intermediate-or high-grade B-cell non-Hodgkin’s lymphoma (NHL), and cervical cancer. All ofthese cancers feature specific infectious agents in their etiology. These agentsare human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus, or HHV-8/KSHV(implicated in Kaposi’s sarcoma), Epstein-Barr virus, or EBV (in primarycentral nervous system lymphoma and a subset of systemic B-cell NHL) andhuman papillomavirus, or HPV (in cervical cancer).[1]

The Effect of HAART

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to clinical trials and NCI resources for cancer in HIV-positive patients.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at www.cancer.gov/cancer_information/pdq/, or contact the Cancer Information Service offices (1-800-4-CANCER).

Although the types of related cancers have not substantially changed sincethe beginning of the AIDS epidemic, the incidence of certain cancers hasmarkedly changed with the use of highly active antiretroviral therapy (HAART).Populations with access to HAART have shown a substantially reduced incidence ofKaposi’s sarcoma and primary central nervous system lymphoma and a muchsmaller decrease in other types of NHL.[2] However, long-term cancer risks areas yet unknown. Kaposi’s sarcoma remains the most commonly diagnosedAIDS-related cancer.[3] NHL, a late and frequently systemic complication ofAIDS, occurs in approximately 5% of cases.[4]

The non-AIDS-defining tumors with particular relevance for the humanimmunodeficiency virus (HIV) population include invasive anal cancer and thepreneoplastic lesions in the anus and cervix. These tumors and lesions are alsoetiologically associated with HPV. The relative risk of invasive anal cancer inHIV-positive men and women is 37.9 and 6.8, respectively.[5] The incidence ofhigh-grade squamous intraepithelial (anogenital or cervical) lesions andinvasive cancer is higher in HIV-positive/HPV-positive individuals than in theHIV-negative/HPV-positive population. In addition, there is an increased risk ofprogression from low-grade to high-grade lesions,[6] and HAART has shown littleeffect on the natural history of these lesions in some studies.[7,8]

The longer life expectancy of HIV-positive individuals with access to HAARTmay increase their cumulative risk of developing cancer. In this context, we maysee an increase in incidence of the following: (1) non-AIDS-defining cancersincluding Hodgkin’s disease and lung cancer (Hodgkin’s disease is currentlythe most frequently diagnosed non-AIDS-defining cancer that is clearly relatedto immunosuppression)[9,5]; (2) progression of high-grade squamousintraepithelial lesions to cancer; (3) T-cell NHL[10]; and (4) possibly aresurgence of Kaposi’s sarcoma. Advances in the understanding of thepathogenesis of AIDS malignancies have allowed the development of targetedtreatment strategies. This, coupled with the decreased morbidity from cancertherapies in HAART-treated HIV-positive patients, provides the opportunity formore targeted or more aggressive regimens that have the potential to lengthenthe patient’s survival.

Treatments of AIDS malignancies have followed conventional cytotoxicchemotherapy approaches and also newer, targeted approaches aimed at interveningin critical pathogenic pathways. The following examples are given for Kaposi’ssarcoma, NHL, and the anogenital dysplasias.

AIDS-Related Kaposi’s Sarcoma

AIDS-related Kaposi’s sarcoma is a tumor of the vascular endothelium thatmay present with cutaneous lesions, either with or without visceral organinvolvement, or with lymphadenopathy. The etiology of the disease includes anintricate relationship between HHV-8/KSHV, aberrant cytokine production,angiogenic factors, and immune dysregulation. Multiple treatment options aimedat each of the players in the pathogenesis of Kaposi’ sarcoma areavailable.[11,12] Local therapies include cryotherapy, laser therapy, localradiation, intralesional injection of chemotherapy, topical alitretinoin gel,and surgical excision. However, because Kaposi’s sarcoma is a systemicdisease, recurrence is common with local therapy.

Disseminated disease is treated with systemic agents, either with drugs orbiologic agents, such as the vinca alkaloids, liposomal anthracyclines,paclitaxel, and interferon-alpha. Therapeutic approaches that target pathogenicpathways have shifted the focus to include: (1) the antiangiogenesis compoundsthalidomide (Thalomid), COL-3, and IM862; (2) retinoids that inhibit interleukin(IL)-6, a cytokine involved in tumor growth of Kaposi’s sarcoma; and(3) IL-12, which has immunomodulatory, antiviral, and antiangiogeniceffects. Another intriguing but as yet untested possibility is the use ofantiviral agents to inhibit HHV-8/KSHV gene expression.

Systemic AIDS-NHL

Systemic AIDS-NHL is a histologically heterogeneous group of malignanciesnormally of B-cell phenotype, although cases of T-cell AIDS-NHL have beendescribed.[9,10] Chronic B-cell stimulation from HIV infection, increasedexpression of cytokines involved in B-cell proliferation, and expression ofcertain EBV genes are involved in various aspects of the pathogenesis of NHL.Standard treatment regimens include cyclophosphamide (Cytoxan, Neosar),doxorubicin HCl, vincristine (Oncovin), and prednisone (CHOP), and variations ofCHOP with infusion regimens such as cyclophosphamide, doxorubicin, and etoposide(CDE) and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin(EPOCH) with some studies reporting response rates above 70%.[13,9] However, therelapse rate is high with most of the bolus CHOP regimens, and overall survivalrates are not clearly improved.

Cytotoxic regimens can be combined with immune system modulators such as IL-2or IL-12, or with monoclonal antibodies against malignant cell targets such asanti-CD20.[14] Other interesting approaches include stem cell transplantation toboth restore immune function and treat lymphoma via a graft-vs-lymphomaeffect[15], or generation of cytotoxic T lymphocytes against EBV genes expressedin NHL.[16]

Anal and Cervical Cancer

Anal and cervical cancers are thought to arise from the progression ofsquamous intraepithelial lesions to invasive tumors. Progression correlates withpersistence of high-risk HPV genotypes. HPV oncogenes E6 and E7 bind to andinactivate the key cell-cycle regulatory proteins p53 and Rb, resulting indysregulated cellular proliferation and transformation.[17] However, a fullymalignant phenotype occurs only in a subset of chronically infected cells,presumably resulting from an accumulation of additional mutations.[18] Treatmentof HPV-related lesions might include surgical removal or local destruction.[19]However, surgery for anal high-grade intraepithelial lesions is not assuccessful as that for cervical high-grade squamous intraepithelial lesions.

The induction of a cell-mediated response to human papillomavirus type 16(HPV16), specifically to the viral protein E7, appears to be protective againstcervical intraepithelial neoplasia (CIN).[20] Thus, vaccines designed to elicitcell-mediated immunity to E6 and E7 may be a basis for immunotherapy ofHPV-related cancers.[21] The AIDS Malignancy Consortium (described below) iscurrently developing a trial to treat anal intraepithelial neoplasia using atherapeutic vaccine designed to elicit a humoral and cellular response toE7-expressing cells in the anal lesion.

The AIDS Malignancy Program

To stimulate and facilitate the integration of knowledge from the biology andepidemiology of the AIDS malignancies with the development of treatmentstrategies, the NCI has developed a multicomponent AIDS Malignancy Program. TheAIDS Malignancy Program was designed to assist the research community instudying the interplay of viruses, immune dysfunction, aberrant growth factorexpression, and the development of cancer in AIDS patients, with the goal ofdeveloping more effective treatment regimens. A description of each component isgiven below.

The AIDS Malignancy Consortium (AMC) was developed in 1995 to facilitatethe rapid evaluation of hypothesis-driven phase I, II, and III multicenterclinical trials that utilize the expertise of both the National Cancer Institute(NCI)- and National Institute of Allergy and Infectious Diseases(NIAID)-sponsored clinical scientists. Their charge is to identifyhypothesis-driven therapeutic approaches for the treatment of malignancies inAIDS patients. These approaches include biologic therapy using IL-2, IL-12,interferon-alpha, monoclonal antibodies directed against B-cell targets,cytotoxic T lymphocytes directed against viral targets, immune-based therapy,stem cell reconstitution, angiogenesis inhibitors, therapeutic vaccines, and thetraditional cytotoxic chemotherapy regimens often in combination with a biologicor immunologic approach. In addition to assessing potential antitumor activityand drug-drug interactions, the AMC also evaluates the impact of therapy onviral load and underlying immune function. Additional information about the AMCcan be obtained at http://www.amc.uab.edu.

The AIDS and Cancer Specimen Bank (ACSB) was established in 1994 toidentify and improve access to well-characterized tissue, fluids, and associateddemographic and clinical data collected from HIV-positive patients andHIV-negative controls, and to encourage and facilitate AIDS-related cancerresearch. The ACSB contains over 30,000 specimens collected from cohort studies,clinical trials, and other research including international sources. Informationon which specimen types are available and how to obtain them can be found at http://acsb.ucsf.edu.

The AIDS Malignancy Working Group (AMWG) was established in 1996 and ischarged with identifying the major areas of research priorities in AIDSmalignancies. It is a multidisciplinary group that includes members from boththe intramural and extramural component of the National Institutes of Health(NIH), researchers outside of NIH, and community representatives. The group isconvened annually to discuss the biomedical opportunities for AIDS malignancies,the clinical gaps in our knowledge, and the mechanisms to move the researchforward and address specific issues. Summaries from recent meetings of the AMWGare available at http://deainfo.nci.nih.gov/advisory/pog/other_wg/aids/.

The International Conference on Malignancies in AIDS and OtherImmunodeficiencies: Basic, Epidemiologic and Clinical Research (ICMAOI) is aforum for the presentation of basic, epidemiologic, and clinical aspects ofresearch on malignancies in HIV-infected and other immunosuppressed individuals.The objective is to enable the exchange of information between laboratory andclinically based investigators to decrease the interval between basic discoveryand clinical application. The scope of the conference includes basic andclinical research on the viral oncology, immunology, genetics, epidemiology,pathogenesis, drug discovery, early diagnosis, and clinical investigation ofmalignant diseases in AIDS and other immunodeficiency states including organtransplantation. The ICMAOI is held annually in the spring on the NIH campus,and the sixth annual conference is scheduled for April 22-24, 2002. Forregistration and additional information, see http://cancer.gov/dctd/aids/conference.

The AIDS Oncology Resources Handbook provides a comprehensive list of theclinical and laboratory research resources that receive NCI funding. A briefsynopsis of the research studies and recent accomplishments is provided as wellas personnel contact information. The Handbook can be viewed in its entirety at http://ctep.cancer.gov/resources/aids.html.

The NIH Inter-Institute Pilot Program for the Development of AIDS-RelatedTherapeutics is a joint effort between the National Institute of Allergy andInfectious Diseases (NIAID) and the NCI. The program is targeted at facilitatingthe preclinical development of therapies for the treatment of HIV disease,AIDS-associated malignancies, opportunistic infections associated with AIDSincluding tuberculosis, and microbicides directed against HIV. The programassists investigators from academic institutions, nonprofit researchinstitutions, and biotechnology and small pharmaceutical companies by providingfacilitated access to the NIH contract resources for therapeutics development.Additional information and application receipt dates can be found at http://dtp.nci.nih.gov/docs/dart/dart.html.

Following is a list of currently active trials sponsored by the NCI.Information about these studies can be obtained from the principal investigatorsor contacts listed for each trial or from Ellen Feigal, MD, at (301) 496-6711 oref30d@nih.gov, or Jodi Black, PhD, at (301) 402-6293 orblackj@mail.nih.gov.

Kaposi’s Sarcoma

Title: Phase III Randomized Study of Paclitaxel Versus DoxorubicinHCL Liposome in Patients with Advanced AIDS-Associated Kaposi's Sarcoma
Protocol Number: AMC-009, CPMC-IRB-9905, E-1D96, SWOG-E1D96
Participating Groups: AIDS-Associated Malignancies Clinical TrialsConsortium; Eastern Cooperative Oncology Group; Southwest Oncology Group
Contact: Jean MacDonald, ECOG, (617) 632-3610 or macdonald. jean@jimmy.harvard.edu, or Jamie H. Von Roenn, MD, (312) 695-6180 or j-vonroenn@northwestern.edu; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Pilot Study to Evaluate the Potential InteractionsBetween Paclitaxel and Protease Inhibitors in Patients With AIDS-RelatedKaposi's Sarcoma
Protocol Number: AMC-014, E-1D95
Participating Groups: AIDS-Associated Malignancies Clinical TrialsConsortium; Eastern Cooperative Oncology Group
Contact: Jean MacDonald, ECOG, (617) 632-3610 or macdonald. jean@jimmy.harvard.edu, or Jamie H. Von Roenn, MD, (312) 695-6180 or j-vonroenn@northwestern.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I/II Trial of BMS-275291 in Patients With HIV-RelatedKaposi’s Sarcoma
Protocol Number: AMC-024, CPMC-IRB-13985
Participating Organization: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Jamie H. Von Roenn, MD, (312) 695-6180 or j-vonroenn@northwestern.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Trial of COL-3 in Patients with HIV-Related Kaposi’sSarcoma
Protocol Number: AMC-027
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Bruce Dezube, MD, (617) 667-7082 or bdezube@caregroup.harvard.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Doxorubicin HCl Liposome andInterleukin-12 in Patients With AIDS-Associated Kaposi's Sarcoma
Protocol Number: NCI-01-C-0067
Participating Institution: National Cancer Institute HIV/AIDS MalignancyBranch
Contact: Richard F. Little, MD, (301) 402-6296 or littler@mail.nih.govLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I/II Pilot Study of Interleukin-12 in Patients WithAIDS-Associated Kaposi's Sarcoma
Protocol Number: NCI-96-C-0113F, NCI-MB-386, NCI-T96-0029N
Participating Institution: National Cancer Institute Medicine Branch
Contact: Robert Yarchoan, MD, (301) 496-8959 (referral number) or ryln@nih.govLatest Information:http://www.cancer.gov/clinical_trials/

AIDS-Related Lymphoma

Title: Phase III Randomized Study of CHOP (Cyclophosphamide,Doxorubicin, Vincristine, and Prednisone) With or Without Rituximab in PatientsWith Previously Untreated HIV-Associated Non-Hodgkin's Lymphoma
Protocol Number: AMC-010, CPMC-IRB-9691, CWRU-AMC-1400, UCLA-9810029
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Lawrence D. Kaplan, MD, (415) 476-4082, ext 409, or lkaplan@php.ucsf.edu; for a complete listingof study contacts, click hereLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Zidovudine, Interleukin-2, and Ganciclovirin Patients With Primary AIDS Related Central Nervous System Lymphoma
Protocol Number: AMC-019
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: William J. Harrington, MD, (305) 243-4994 or wharring@mednet.med.miami.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Pilot Study of Autologous Peripheral Blood StemCell Transplantation in Patients With Recurrent or Refractory AIDS-RelatedLymphoma
Protocol Number: AMC-020
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: David T. Scadden, MD, (617) 726-5615 or scadden.david@mgh.harvard.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Allogeneic Peripheral Blood Stem CellTransplantation Followed By Delayed Donor Leukocyte Infusion in Patients WithAIDS-Related Lymphoma
Protocol Number: AMC-028
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: David T. Scadden, MD, (617) 726-5615 or scadden.david@mgh.harvard.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase I Study of Bryostatin 1 and Vincristine in PatientsWith Recurrent or Refractory HIV-Related B-Cell Lymphoma
Protocol Number: AMC-029
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Scot C. Remick, MD, (216) 844-1210 (direct), (216) 844-1196(clinic secretary), or scr@po.cwru.eduLatest Information:http://www.cancer.gov/clinical_trials/

Title: Phase II Study of Etoposide, Vincristine, Cyclophosphamide,Doxorubicin, and Rituximab in Patients With Previously Untreated AIDS-RelatedNon-Hodgkin's Lymphoma
Protocol Number: NCI-01-C-0030, NCI-2890
Participating Institution: National Cancer Institute Medicine Branch
Contact: Wyndham H. Wilson, MD, (301) 435-2415 or wilsonw@mail.nih.gov,or Nicole Drbohlav and Therese White, (301) 496-1211
Latest Information:http://www.cancer.gov/clinical_trials/

Title: A Randomized Phase II Trial of EPOCH given either Concurrently orSequentially with Rituximab in Patients with Intermediate- or High-gradeHIV-associated B-cell Non-Hodgkin’s Lymphoma
Protocol Number: AMC-034 (in review)
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Joseph A. Sparano, MD, (718) 904-2555 or fax (718) 904-2892 or jsparano@montefiore.org

Title: Phase II Trial of Induction Therapy With EPOCH Chemotherapy andMaintenance Therapy With Combivir/Interferon for HTLV-1 Associated T-cellNon-Hodgkin’s Lymphoma
Protocol Number: AMC-033 (in review)
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Lee Ratner, MD, (314) 362-8836, fax (314) 747-2797, or lratner@imgate.wustl.edu

Anal Neoplasia

Title: A Phase I/II Trial of SGN-00101 in the Treatment of High-gradeAnal Intraepithelial Neoplasia in HIV-Positive Individuals
Protocol Number: AMC-035 (in review)
Participating Institution: AIDS-Associated Malignancies Clinical TrialsConsortium
Contact: Joel Palefsky, MD, (415) 476-1574, fax (415) 476-0986, or joelp@medicine.ucsf.edu

References:

1. Feigal EG: AIDS-associated malignancies; research perspectives. BiochimBiophys Acta 1423:C1-C9, 1998.

2. International Collaboration on HIV and Cancer: Highly activeantiretroviral therapy and incidence of cancer in human immunodeficiencyvirus-infected adults. J Natl Cancer Inst 92:1823-1830, 2000.

3. Jones JL, Hanson DL, Dworkin MS, et al: Incidence and trends in Kaposi’ssarcoma in the era of effective antiretroviral therapy. J Acquir Immune Defic Syndr 24:270-274, 2000.

4. IARC monographs on the evaluation of carcinogenic risks to humans: HumanImmunodeficiency viruses and human T-cell lymphotropic viruses, vol 67. Lyon,IARC,1996.

5. Frisch M, Biggar RJ, Engels EA, et al: Association of cancer withAIDS-related immunosuppression in adults. JAMA 285:1736-1745, 2001.

6. Martin F, Bower M: Anal intraepithelial neoplasia in HIV positive people.Sex Transm Inf 77:327-331, 2001.

7. Palefsky JM, Holly EA, Ralston ML, et al: Effect of highly activeantiretroviral therapy on the natural history of anal squamous intraepitheliallesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr28:422-428, 2001.

8. Lillo FB, Ferrari D, Veglia F, et al: Human papillomavirus infection andassociated cervical disease in human immunodeficiency virus-infected women:Effect of highly active antiretroviral therapy. J Infect Dis 184:547-551, 2001.

9. Tirelli U, Spina M, Gianluca G, et al: Epidemiological, biological, andclinical features of HIV-related lymphomas in the era of highly activeantiretroviral therapy. AIDS 14:1675-1688, 2000.

10. Levine AM, Seneviratne L, Espina BM, et al: Evolving characteristics ofAIDS-related lymphoma. Blood 96:4084-4090, 2000.

11. Levine AM, Tulpule A: Clinical aspects and management of AIDS-relatedKaposi’s sarcoma. Eur J Cancer 37:1288-1295,2001.

12. Hermans P: Kaposi’s sarcoma in HIV-infected patients; treatmentoptions. HIV Medicine 1:137-142, 2001.

13. Little RF, Yarchoan R, Wilson WH: Systemic chemotherapy forHIV-associated lymphoma in the era of highly active antiretroviral therapy. CurrOpin Oncol 12:438-444, 2000.

14. Demidem A, Hanna N, Hariharan H, et al: Chimeric anti-CD20 antibody (IDECErituximab) is apoptotic and sensitizes drug-resistant human B-cell lymphomas andAIDS-related lymphomas to the cytotoxic effect of CDDP, VP-16, and toxins. FASEBJ 9:A206, 1995.

15. Krishnan A, Molina A, Zaia J, et al: Autologous stem cell transplantationfor HIV-associated lymphoma. Blood 98:3857-3859, 2001.

16. Savoldo B, Heslop HE, Rooney CM: The use of cytotoxic T cells for theprevention and treatment of Epstein-Barr virus induced lymphoma in transplantrecipients. Leuk Lymphoma 39:455-464, 2000.

17. Palefsky JM, Holly EA: Molecular virology and epidemiology of humanpapillomavirus and cervical cancer. Cancer Epidemiol Biomarkers Prev 4:415-428,1995.

18. Zur Hausen, H: Immortalisation of human cells and their malignantconversion by high-risk human papillomavirus genotypes. Semin Cancer Biol9:405-411, 1999.

19. Palefsky JM: Anal squamous intraepithelial lesions in humanimmunodeficiency virus-positive men and women. Semin Oncol 27:471-479, 2000.

20. Nakagawa M, Stites DP, Palefsky JM, et al: CD4 positive as well asCD8 positive cytotoxic T lymphocytes contribute to human papillomavirus type 16E6 and E7 responses. Clin Diagn Lab Immunol 6:494-498,
1999.

21. Del Mistro A, Bianchi LC: HPV-related neoplasias in HIV-infectedindividuals. Eur J Cancer 37:1227-1235, 2001.