Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 13, No. suppl_1, 1-4, January 2008; doi:10.1634/theoncologist.13-S1-1
© 2008 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bunn, P. A.
Right arrow Articles by Thatcher, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bunn, P. A., Jr.
Right arrow Articles by Thatcher, N.

Introduction

Paul A. Bunn, Jr.a, Nick Thatcherb

aUniversity of Colorado Cancer Center, Aurora, Colorado, USA; bDepartment of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom

Key Words. Non-small cell lung carcinoma • Antineoplastic agents • Angiogenesis inhibitors Protein kinase inhibitors • Antimetabolites

Correspondence: Nick Thatcher, M.B., B.Chir., Ph.D., F.R.C.P., Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK. Telephone: 44-161-446-3848/3749; Fax: 44-161-446-8000; e-mail: nick.thatcher{at}christie-tr.nwestnhs.uk

Received September 24, 2007; accepted for publication September 24, 2007.

Disclosure: N.T. has received honoraria and research support from AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Merck, and Roche. P.B. has received honoraria from OSI/Genentech/Roche, Eli Lilly and Company, AstraZeneca, Imclone/BMS, and Sanofi-Aventis.


   ABSTRACT
Top
 Abstract
Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 
Lung cancer is the most common cancer and a highly lethal disease, with improvements in survival rates being dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease. Non-small cell lung cancer (NSCLC) represents around 80% of all lung cancers, and unfortunately at diagnosis most patients have advanced unresectable disease with a very poor prognosis. Indeed, 30%–40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment. Current U.S. Food and Drug Administration–approved second-line treatments are docetaxel (a taxane), pemetrexed (a folate antimetabolite), and erlotinib (an epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]). Gefitinib, another EGFR TKI, currently has only limited use in North America and is not available in Europe. These and other new molecular-target-specific agents may have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Overexpression of EGFR is reported to occur in 40%–80% of NSCLC cases, and EGFR mutations are associated with a significantly higher response rate and longer duration of response following treatment with EGFR TKIs. Another option is antiangiogenesis: the growth and persistence of solid tumors and their metastases are angiogenesis dependent, and so antiangiogenic therapies have been developed, such as the use of TKIs that block the vascular endothelial growth factor receptor. In fact, many commonly used chemotherapeutic drugs have antiangiogenic activity. Ongoing studies are focusing on patient selection and targeted therapies, and there are many new agents undergoing clinical trials.


   INTRODUCTION
Top
 Abstract
 Introduction
Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 
Lung cancer is the most common cancer in the world today, in terms of both incidence (in 2002 there were 1.35 million cases diagnosed, representing 12.4% of all new cancers) and mortality (1.18 million deaths in 2002, or 17.6% of the world's total cancer deaths that year) [1]. It is a highly lethal disease: the 5-year survival rate measured by the Surveillance, Epidemiology, and End Results (SEER) program in the U.S. is 15% [2], and Europe's average is 10% [3], which is not a great improvement over the 8.9% observed in developing countries. Improvements in 5-year survival rates are dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease.

Non-small cell lung cancer (NSCLC)—consisting of squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma—represents around 80% of all lung cancers. Unfortunately, most patients have advanced, unresectable disease at diagnosis, which has a very poor prognosis. Before 1980, radiotherapy was thought to be the only option for advanced disease, but a few years before the turn of the millennium a meta-analysis of NSCLC trials demonstrated a survival benefit with platinum-based chemotherapy. Since then, meta-analyses have shown that platinum-based doublets can improve survival in stage II–IV NSCLC, and some data suggest that this may also be true in stage IB disease. New chemotherapy agents and better supportive care measures have allowed more patients to benefit from chemotherapy with less toxicity [4]. New "targeted therapies" directed against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways have also improved the prognosis for specific patient subpopulations. However, 30%–40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment.


   SECOND-LINE THERAPIES
Top
 Abstract
 Introduction
 Second-Line Therapies
Targeted Therapy
 Acknowledgments
 References
 
Docetaxel, a taxane and a semisynthetic analogue of paclitaxel, was approved by the U.S. Food and Drug Administration (FDA) for the second-line treatment of NSCLC after studies showed a response rate of 17% for previously treated patients, with a median survival time of 8 months. A weekly dosing regimen has been proposed as being more convenient and causing less adverse effects than the standard 3-weekly schedule, and recent trials have shown that while weekly docetaxel does not result in better survival rates when compared with a 3-week docetaxel regimen, it does produce better compliance and response rates, and a significantly lower rate of neutropenia [5–8].

In 2006, two other agents joined docetaxel as FDA-approved second-line therapies for NSCLC [9]. The first of these new chemotherapy agents to be approved was pemetrexed, a folate antimetabolite administered with folic acid and vitamin B12, which has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel [10]. In a randomized phase III study directly comparing docetaxel and pemetrexed in previously treated patients, the median survival time was 8.3 months for pemetrexed-treated patients and 7.9 months for docetaxel-treated patients. The response rates were 9.1% with pemetrexed and 8.8% with docetaxel, and both drugs were associated with a progression-free survival time of 2.9 months [11]. Pemetrexed has a more favorable safety profile than docetaxel, causing less alopecia, neutropenia, neutropenic infections, need for G-CSF, and hospitalization for neutropenic fever.

Erlotinib, the most recent EGFR tyrosine kinase inhibitor (TKI) to be approved for second- (and third)-line treatment of patients with locally advanced or metastatic NSCLC, has shown a survival advantage over placebo in NSCLC patients after first- or second-line chemotherapy. With an objective response rate of around 8%–12%, regardless of type or number of prior chemotherapy regimens, and a median survival time of 6.7–8.4 months (1-year survival rate of 30%–40%), results with erlotinib use are encouraging when compared with other therapies in similar heavily pretreated patients [12, 13].

The other FDA-approved EGFR TKI, gefitinib, currently has its use limited in the U.S. and Canada to patients who are currently benefiting, or have previously benefited, from gefitinib treatment, or those involved in an access program. The labeling was changed in June 2005 after a review of studies revealed that, unlike erlotinib, the survival benefit from gefitinib (hazard ratio, 0.89) failed to reach significance except in some subsets of patients (those of Asian ethnicity, those who have never smoked [14]). While gefitinib has been approved elsewhere internationally, it is not available in the European Union [15].


   TARGETED THERAPY
Top
 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
Acknowledgments
 References
 
Response rates to chemotherapy in NSCLC are modest, reflecting the disease's high molecular heterogeneity. Increased knowledge about these molecular properties has facilitated the development of targeted therapies for specific genetic profiles. Whereas chemotherapeutic drugs affect all dividing cells, agents that selectively target specific receptors, such as EGFR, act mainly on malignant cells, where such receptors are overexpressed compared with their limited role in normal tissue. These molecular-target–specific agents therefore have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells.

A range of new targeted therapies is being investigated, including (a) inhibitors of the proteosomal complex, (b) histone deacetylase, (c) mammalian target of rapamycin pathway, (d) the eicosanoid pathway, (e) the protein kinase C (PKC)/Ras/mitogen-activated protein kinase pathway, (f) Raf kinase isoforms, (g) cyclooxygenase-2, and (h) other growth factor receptor–mediated signaling. Other approaches have failed in phase III studies (e.g., PKC and matrix metalloproteinase inhibitors), but this may be due to lack of appropriate patient selection [16–19].

With such targeted therapies, it can be speculated that treatment could be chosen according to which would be most effective for the specific tumor, for example, 5-fluorouracil–derived agents could be used for tumors with a low level of expression of thymidylate synthase; cisplatin and carboplatin would be preferential for tumors with a low level of expression of excision repair cross complementing-1; gemcitabine would be more useful for tumors with a low level of expression of ribonucleotide reductase; and gefitinib and erlotinib would best be used for tumors with EGFR mutations or increased EGFR gene copy numbers [20].

Overexpression of EGFR is reported to occur in 40%–80% of NSCLC cases [21], and patients with somatic mutations of the EGFR gene have a significantly higher response rate to treatment with EGFR TKIs than patients with wildtype EGFR [22]. Additionally, of those patients achieving a partial response, patients with EGFR mutations show a trend toward a longer duration of response in comparison with patients without EGFR mutations. EGFR gene amplification detected by fluorescence in situ hybridization can also be used to select patients for EGFR TKI therapy [23, 24]. Other EGFR TKIs are currently under investigation in phase I/II trials, many of which have differing selectivities for the various members of the human EGFR family [25].

Higher response rates to EGFR TKIs have also been seen in other patient subgroups, such as women, those with an Asian background, never-smokers, and patients with adenocarcinoma. This may be a result of an association between these clinical characteristics and the EGFR mutations (usually amino acid deletions or substitutions) thought to occur on exons 19 and 21 [22, 26].

The VEGF pathway forms another target for treatment. It has been 35 years since tumor vasculature was first singled out as a good target for therapy development [27], and since then it has been shown that the growth and persistence of solid tumors and their metastases are indeed angiogenesis dependent [28]. Antiangiogenic therapy, such as the use of TKIs that block the VEGFR, aims to disrupt existing capillaries that feed a tumor and prevent new vessels from forming around it [28]. Studies using VEGF pathway inhibitors as monotherapy have demonstrated low objective response rates; antiangiogenic agents can be effective in inhibiting tumor growth, but in most studies they do not destroy tumors [29], although this can be overcome by combining angiogenesis inhibitors with cytotoxic therapies [30–35]. Bevacizumab, a monoclonal antibody targeting VEGF that was recently approved for the treatment of colorectal cancer, extended survival in a recent clinical trial when used in combination with chemotherapy for selected patients with NSCLC with nonsquamous histology and lacking brain metastases or bleeding [36]. Several small-molecule VEGFR TKIs have activity in NSCLC, and additional trials are in progress [37]. These antiangiogenic agents are also being studied in small-cell lung cancer. There is also evidence that many commonly used chemotherapeutic drugs have antiangiogenic activity [38]; the question is how best to administer these agents to use both their cytotoxic and antiangiogenic properties [39, 40]. Angiogenesis inhibitors are most effective with a dose schedule that maintains a constant concentration in the circulation [40], and the use of gene therapy to deliver antiangiogenesis genes has shown promise in preclinical models [35, 41, 42].

These types of advances in the understanding of molecular processes in NSCLC are driving new research. Screening patients for various factors before treatment may allow predictions about the clinical benefit of the treatment. For example, DNA in pleural effusion fluid can be used to detect EGFR mutations [43]. Another potential independent prognostic factor in patients with NSCLC is glucose metabolic activity, which closely reflects response to gefitinib therapy. As such, fluorodeoxyglucose (FDG)–positron emission tomography, an imaging method that uses the higher glycolytic rate of tumor cells, may be a valuable clinical tool; increased FDG uptake is an independent prognostic factor in patients with International Union against Cancer stage I/II NSCLC, and less distinctively so for stage III tumors [44, 45].

This supplement has been put together to provide an overview of currently available and investigational treatment regimens for NSCLC. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of ongoing studies, and there are many new agents undergoing clinical trials. These developments are moving the field into an era of optimism in taking on the many remaining challenges of managing NSCLC.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
References
 
The authors would like to thank Remedica Medical Education and Publishing, London, UK, for its support during the preparation of this manuscript.


   REFERENCES
Top
 Abstract
 Introduction
 Second-Line Therapies
 Targeted Therapy
 Acknowledgments
 References
 

  1. Parkin DM, Bray F, Ferlay J et al. Global statistics cancer, 2002. CA Cancer J Clin 2005;55:74–108.[Abstract/Free Full Text]
  2. Ries LAG, Eisner MP, Kosary CL et al, eds. SEER Cancer Statistics Review, 1975–2001. Bethesda, MD: National Cancer Institute, 2004. Available at http://seer.cancer.gov/csr/1975_2001/. Accessed February 23, 2007.
  3. Sant M, Aareleid T, Berrino F et al. EUROCARE-3: Survival of cancer patients diagnosed 1990–94'results and commentary. Ann Oncol 2003;14(suppl 5):v61–v118.[CrossRef][Medline]
  4. Weiss GJ, Bunn PA Jr, Camidge DR. From radiotherapy to targeted therapy: 20 years in the management of non-small-cell lung cancer. Oncology (Williston Park) 2006;20:1515–1524; discussion 1524–1525, 1530, 1535.[Medline]
  5. Bria E, Cuppone F, Ciccarese M et al. Weekly docetaxel as second line chemotherapy for advanced non-small-cell lung cancer: Meta-analysis of randomized trials. Cancer Treat Rev 2006;32:583–587.[CrossRef][Medline]
  6. Chen YM, Shih JF, Perng RP et al. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest 2006;129:1031–1038.[CrossRef][Medline]
  7. Camps C, Massuti B, Jimenez A et al. Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: A Spanish Lung Cancer Group trial. Ann Oncol 2006;17:467–472.[Abstract/Free Full Text]
  8. Gridelli C, Gallo C, Di Maio M et al. A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study. Br J Cancer 2004;91:1996–2004.[CrossRef][Medline]
  9. Ho C, Davies AM, Lara PN Jr et al. Second-line treatment for advanced-stage non-small-cell lung cancer: Current and future options. Clin Lung Cancer 2006;7(suppl 4):S118–S125.[Medline]
  10. Scagliotti G. An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer. Expert Opin Pharmacother 2005;6:2855–2866.[CrossRef][Medline]
  11. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.[Abstract/Free Full Text]
  12. Pérez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238–3247.[Abstract/Free Full Text]
  13. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
  14. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Gefitinib (marketed as Iressa) Information. FDA Alert. 2005. Available at http://www.fda.gov/cder/drug/infopage/gefitinib/default.htm. Accessed February 22, 2007.
  15. AstraZeneca Oncology. Iressa Website. 2006. Availability. Accessed March 8, 2007.
  16. Ramalingam S, Belani CP. Recent advances in targeted therapy for non-small cell lung cancer. Expert Opin Ther Targets 2007;11:245–257.[CrossRef][Medline]
  17. Auberger J, Loeffler-Ragg J, Wurzer W et al. Targeted therapies in non-small cell lung cancer: Proven concepts and unfulfilled promises. Curr Cancer Drug Targets 2006;6:271–294.[CrossRef][Medline]
  18. Gollob JA, Wilhelm S, Carter C et al. Role of Raf kinase in cancer: Therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006;33:392–406.[CrossRef][Medline]
  19. Spicer J, Harper P. Targeted therapies for non-small cell lung cancer. Int J Clin Pract 2005;59:1055–1062.[CrossRef][Medline]
  20. Huang CL, Yokomise H, Fukushima M et al. Tailor-made chemotherapy for non-small cell lung cancer patients. Future Oncol 2006;2:289–299.[CrossRef][Medline]
  21. Salomon DS, Brandt R, Ciardiello F et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.[Medline]
  22. von Eyben FE. Epidermal growth factor receptor inhibition and non-small cell lung cancer. Crit Rev Clin Lab Sci 2006;43:291–323.[CrossRef][Medline]
  23. Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–655.[Abstract/Free Full Text]
  24. Hirsch FR, Varella-Garcia M, McCoy J et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group study. J Clin Oncol 2005;23:6838–6845.[Abstract/Free Full Text]
  25. Silvestri GA, Rivera MP. Targeted therapy for the treatment of advanced non-small cell lung cancer: A review of the epidermal growth factor receptor antagonists. Chest 2005;128:3975–3984.[CrossRef][Medline]
  26. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
  27. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.[Medline]
  28. Marx J. Angiogenesis: A boost for tumor starvation. Science 2003;301:452–454.[Abstract/Free Full Text]
  29. Reimer CL, Agata N, Tammam JG et al. Antineoplastic effects of chemotherapeutic agents are potentiated by NM-3, an inhibitor of angiogenesis. Cancer Res 2002;62:789–795.[Abstract/Free Full Text]
  30. Teicher BA, Sotomayor EA, Huang ZD. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 1992;52:6702–6704.[Abstract/Free Full Text]
  31. Kato T, Sato K, Kakinuma H et al. Enhanced suppression of tumor growth by combination of angiogenesis inhibitor O-(chloroacetylcarbamoyl)fumagillol (TNP-470) and cytotoxic agents in mice. Cancer Res 1994;54:5143–5147.[Abstract/Free Full Text]
  32. Schiller JH, Bittner G. Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: Effects on tumor neovascularization. Clin Cancer Res 1999;5:4287–4294.[Abstract/Free Full Text]
  33. Strawn LM, Kabbinavar F, Schwartz DP et al. Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts. Clin Cancer Res 2000;6:2931–2940.[Abstract/Free Full Text]
  34. Browder T, Butterfield CE, Kräling BM et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878–1886.[Abstract/Free Full Text]
  35. Li G, Tian L, Hou JM et al. Improved therapeutic effectiveness by combining recombinant CXC chemokine ligand 10 with cisplatin in solid tumors. Clin Cancer Res 2005;11:4217–4224.[Abstract/Free Full Text]
  36. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550.[Abstract/Free Full Text]
  37. Socinski MA, Novello S, Sanchez JM et al. Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II trial. J Clin Oncol (Meeting Abstracts) 2006;24:7001.
  38. Miller KD, Sweeney CJ, Sledge GW Jr. Redefining the target: Chemotherapeutics as antiangiogenics. J Clin Oncol 2001;19:1195–1206.[Abstract/Free Full Text]
  39. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685–693.[CrossRef][Medline]
  40. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002;2:727–739.[CrossRef][Medline]
  41. Li YY, Qian GS, Huang GJ et al. Enhancement of antiangiogenic effects of human canstatin with a hypoxia-regulated transgene vector in lung cancer model. Cancer J 2006;12:136–146.[Medline]
  42. Luo X, Slater JM, Gridley DS. Enhancement of radiation effects by pXLG-mEndo in a lung carcinoma model. Int J Radiat Oncol Biol Phys 2005;63:553–564.[CrossRef][Medline]
  43. Kimura H, Fujiwara Y, Sone T et al. EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib. Br J Cancer 2006;95:1390–1395.[CrossRef][Medline]
  44. Su H, Bodenstein C, Dumont RA et al. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res 2006;12:5659–5667.[Abstract/Free Full Text]
  45. Eschmann SM, Friedel G, Paulsen F et al. Is standardised (18)F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer? Eur J Nucl Med Mol Imaging 2006;33:263–269.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bunn, P. A.
Right arrow Articles by Thatcher, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bunn, P. A., Jr.
Right arrow Articles by Thatcher, N.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS