Cancer Treatment

PET for esophageal cancer

The imaging modalities commonly used for the diagnosis and staging of esophageal cancer are upper GI study, endoscopy, endoscopic ultrasound, CT, and PET.
PET is superior to CT and EUS combined in diagnosing stage IV disease. In a study by Flamen et al., PET was more accurate 82% vs. 64% for CT and EUS combined in staging esophageal cancer. 18 out of 74 patients had discordant findings between PET vs. CT and EUS. PET was correct in 16 out of 18 patients based on surgical findings. It upstaged 11 patients and downstaged 5 patients. In 3 other studies PET demonstrated distant metastasis not seen on conventional imaging in (21/105 pts.).

NCCN recommends PET for preoperative staging only, not for restaging. While the studies on detection of distant disease suggest better diagnostic performance for PET over CT, the available body of evidence is small. Only one study clearly avoided verification bias, only one clearly interpreted PET blind to the reference standard, and none clearly interpreted the reference standard blind to PET.
Regarding evaluation of treatment response, one study of 14 patients was identified. While PET found evidence of response not shown on CT, these data are insufficient to permit conclusions regarding the value of PET in evaluating response to treatment. Various TEC Assessments have not recommended PET for restaging.

Skehan SJ, Brown AL, Thompson M, Young JE, Coates G, Nahmias C. Imaging features of primary and recurrent esophageal cancer at FDG PET. Radiographics. 2000 May-Jun;20(3):713-23.

5. Flamen P, Van Cutsem E, Lerut A, Cambier JP, Haustermans K, Bormans G, De Leyn P, Van Raemdonck D, De Wever W, Ectors N, Maes A, Mortelmans L. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 2002 Mar;13(3):361-8.

Danish Centre for Evaluation, Health Technology Assessment (DACEHTA). Paper concerning clinical PET-scanning using FDG - with focus on diagnosis of cancer. Copenhagen, Denmark: DACEHTA; 2001.

Deutsches Institut für Medizinische Dokumentation und Information (DIMDI). [Economic evaluation of positron-emission-tomography: a health economic HTA-report]. Cologne, Germany: DIMDI; 2001.
Health Technology Board for Scotland (HTBS). Health Technology Assessment Advice 2: Positron emission tomography (PET) imaging in cancer management. Glasgow, Scotland: HTBS; 2002.

BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). FDG positron emission tomography for evaluating esophageal cancer. TEC Assessment Program. Chicago, IL: BCBSA; 2001;16(21).

Decitabine and epigenetic therapy for solid cancers

Lay search: Decitabine is being studies for :epigenetic" therapy of solid cacners.

Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2´-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth.

Currenlty Decitabine is FDA approved for myedlodysplaisa. Because of the aforementioned emchanism of action, there is interest in studying it in colorectal and oterh solid cancers. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies.

Robert Brown, Jane A Plumb Demethylation of DNA by decitabine in cancer chemotherapyExpert Review of Anticancer Therapy August 2004, Vol. 4, No. 4, Pages 501-510

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O'Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

http://jco.ascopubs.org/cgi/reprint/JCO.2004.01.947v1.pdf

Adis Decitabine: 2'-Deoxy-5-azacytidine, Aza dC, DAC, Dezocitidine, NSC 127716. R&D Profile Drugs in R & D. 4(6):352-358, 2003.

Jean-Pierre J. Issa DNA Methylation as a Therapeutic Target in Cancer Clinical Cancer Research 13, 1634-1637, March 15, 2007.

Preoperative chemotherapy for esophageal cancer

Lay Summary: Chemotherapy or chemotherapy with radiation are standard of care for esophageal cancer that has not spread.

The role of preoperative chemoradiation for esophageal cancer is well established. Two meta-analyses comprised of the results from 15 randomized controlled trials, as well as pooling performed by the Gastrointestinal Cancer Disease Site Group, all detected a statistically significant difference in survival favouring preoperative chemoradiotherapy, but at three years only. Therefore, the Gastrointestinal Cancer Disease Site Group acknowledges there is evidence indicating survival benefits with either neoadjuvant chemotherapy or chemoradiotherapy compared with surgery alone; however, individual trial results are inconsistent. Based on the majority of the evidence available at this time, the Gastrointestinal Cancer Disease Site Group continues to support the stated recommendations and will continue to examine new evidence as it becomes available. NCCN does list chemoradiation for resectable esophageal cancer. It lists cisplatin/5FU or a "taxane based regimen" as acceptable alternatives.

Malthaner RA, Collin S, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database of Systematic Reviews 2001, Issue 1

nccn.org, esophageal cancer

Oncotech chemosensitivity and chemoresistance assays

Lay Summary: Chemosensitivity assays are controversial but most experts believe that they do not reliably assist in selecting chemotherapy. There is more evidence for chemoresistance assays but this also remains disputed.

Oncotech ER is a form of chemosensitivity testing, or rather, a modification that tests resistance to chemo rather than sensitivity. The recent article by Schrag et al1 criticized the field of chemosensitivity and drug resistance, concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays should be paid for. This became a casue celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The Amreican Society of Clnical Oncology vigorously objected and recommended: "
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority."  I believe that the So. California branch of ASCO disssented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

The Extreme Drug Resistance Assay (EDR) Assay is a laboratory test performed on a patient's tumor cells. This lab test is claimed to determine the probability of a tumor's resistance to a specific chemotherapy drug. If the tumor cells grow in the presence of very high concentrations of chemotherapy drug, then the cancer cells are considered resistant to that drug.

Drug sensitivity and resistance assays have been examined for their potential utility in ovarian cancer by a number of clinical investigators. Unfortunately, analysis of these studies has suffered greatly from the absence of an appropriate control population. The majority of these trials have compared the survival of individuals whose treatment was selected by a particular assay with a historical/retrospective patient group treated at the same institution. A report in the Gynecologic Cancer session described an important attempt by investigators in Europe to directly address the value of the adenosine triphosphate (ATP)-based tumor chemosensitivity assay, by randomizing patients with platinum-resistant ovarian cancer (n = 180) to either "assay-directed therapy" or the treatment of the "physician's choice". The objective response rate was 40.5% for the assay-directed group vs 31.5% for the physician's choice of treatment. Progression-free survival (intention-to-treat analysis) was 104 days in the assay-directed vs 93 days in the physician's choice groups. In addition, there was no difference in overall survival between the strategies. This study provides support for the conclusion that the ATP-based tumor chemosensitivity assay is not superior to physician's choice in the selection of chemotherapy in women with platinum-resistant ovarian cancer.Some experts claim that resistance assays are different from chemosensitivity assays and Medicare does cover them. However, this distinction has not been sufficiently demonstrated and most expersts vigorously dispute this.

In conclusion, the technologies and the questions that they raise are quite different. It Oncotech Sensitivy testing not yet been  recommended by professional societies and gudielines pending completion of a phase III trial. With Oncotech ER the situation is as described above.

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 - 5259.

M. Markman Chemosensitivity and Chemoresistance Testing
J. Clin. Oncol., October 10, 2005; 23(29): 7363 - 7364.

R. Nagourney Chemosensitivity and Resistance Assays: A Systematic Review?
J. Clin. Oncol., May 20, 2005; 23(15): 3640 - 3641.

J. P. Fruehauf and D. S. Alberts
In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins
J. Clin. Oncol., May 20, 2005; 23(15): 3641 - 3643.
 
H. S. Wieand
Chemotherapy Sensitivity and Response Assays: Are the ASCO Guidelines for Clinical Trial Design Too Restrictive?
J. Clin. Oncol., May 20, 2005; 23(15): 3643 - 3644.
 
M. Castro Resisting a Fundamentalist Policy
J. Clin. Oncol., May 20, 2005; 23(15): 3645 - 3646.

Erbitux for esophageal cancer

More than 50% of patients with esophageal cancer have metastatic disease at presentation. The use of chemotherapy for this patient group is increasing with the intention of local and distant tumor control, improving quality of life and prolongation of survival. A number of agents have been investigated as sole therapy for esophageal cancer, including cisplatin, irinotecan, bleomycin, mitomycin, 5-fluorouracil, paclitaxel, methotrexate, vinorelbine, mitoguazone, vindesine, doxorubicin, and etoposide. Phase II trials have demonstrated responses of 15% to 30% for these agents, with cisplatin, mitomycin, 5-fluorouracil, paclitaxel, and vindesine being the most active. The responses have been short lived and have not led to any meaningful prolongation of survival. Five randomized controlled trials have not shown prolonged survival but occasional palliation can be achieved. There is a need for well designed, adequately powered, phase III trials comparing chemotherapy versus best supportive care for patients with metastatic esophageal cancer. Chemotherapy agents with promising response rates and tolerable toxicity are cisplatin, 5-fluorouracil (5-FU), paclitaxel and antracyclins. Combining taxotere and Xeloda is not supported by significant literature.

NCCN lists options for metastatic disease in a carefully worded way (without addressing specific protocols), with recommendations for oxaliplatin, cisplatin, 5FU, taxane or irinotecan (Camptosar) based therapy. The regimen proposed in this case is Folfiri with Erbitux. This is a regimen approved for 2nd line colon cancer.

We eagerly await the results of the many cooperative group and single-institution clinical trials exploring the role of cetuximab in esophageal cancer. These include a South-west Oncology Group (SWOG) trial of cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma, a Memorial Sloan-Kettering Cancer Center study of cetuximab in irinotecan/cisplatin-refractory patients with metastatic esophageal cancer and a Dana-Farber Cancer Institute preoperative trial with cisplatin, irinotecan, cetuximab, and radiation in locally advanced esophageal cancer. In two phase I studies, EGFR-directed antibodies have shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR mAb EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had a durable, 6-month PR. In addition, a phase I trial with ABX-EGF, a high-affinity, fully human IgG2 EGFR mAb, reported stable disease for 7 months in one esophageal cancer patient. Two recent studies presented at the 2006 meeting of the American Society for Therapeutic Radiation and Oncology (ASTRO) suggest that Erbitux® (cetuximab) can be safely added to combination chemotherapy regimens for rectal and esophageal cancer. However, these are studies with radiation and in early phase II.

The Cochrane Database of Systematic Reviews 2006 Issue 4 Chemotherapy for metastatic (spread to other parts of the body) cancer which originates in the esophagus.

Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2003;(4):CD001556.

NCCN.ORG, Esophageal Cancer

Roedel C, Arnold D, Hipp M, et al. Cetuximab in combination with capecitabine, oxaliplatin and concomitant radiotherapy (Cet-Capox-RT) as preoperative therapy for rectal cancer. International Journal of  Radiation Oncology* Biology*Physics. 2006;66, issue 3, Supplement:S82-S83, abstract 147.

Suntharalingam M, Dipretrillo T, Wanebo H, et al. A phase II trial evaluating the efficacy of weekly cetuximab, paclitaxel, carboplatin and daily RT in esophageal cancer. International Journal of  Radiation Oncology* Biology*Physics. 2006;66, issue 3, Supplement:S22-S23, abstract 40.

Vanhoefer U, Tewes M, Rojo F et al. Phase I study of the humanized anti-epidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 2004;22:175–184

Figlin RA, Belldegrun AS, Crawford J et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002;21:10a.

http://www.clinicaltrials.gov/ct/show/NCT00130689;jsessionid=D8926040CFFCDC3A4C970110B75A3302?order=20

William P. Tew, David P. Kelsen, David H. Ilson Targeted Therapies for Esophageal Cancer The Oncologist, Vol. 10, No. 8, 590-601, September 2005;

Vanhoefer U, Tewes M, Rojo F et al. Phase I study of the humanized anti-epidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 2004;22:175–184.[Abstract/Free Full Text]

Figlin RA, Belldegrun AS, Crawford J et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002;21:10a.

J. Tabernero*, T. Macarulla, F. J. Ramos and J. Baselga Novel targeted therapies in the treatment of gastric and esophageal cancer Annals of Oncology 2005 16(11):1740-1748;