Cancer Treatment Today » Gastrointestinal Malignancies

Erbitux for gastric cancer – pro

M Levin, MD — Wed, 29 May 2013 02:13:57 +0000

Epidermal growth factor receptor (EGFR) is over-expressed in a significant proportion of esophageal and gastric carcinomas and there has been significant interest in targeting it. Unfortunately, it has not yet shown much progress. A phase II study by Chan et al showed minimal clinical activity of cetuximab. A recent phase III trial, EXPAND (Erbitux in Combination With Xeloda and Cisplatin in Advanced Esophagogastric Cancer), involved 904 patients in 24 countries in Asia Pacific, Europe, and Latin America, and in Japan. Patients had unresectable advanced cancer of the stomach or gastroesophageal junction, and had received no previous chemotherapy or radiotherapy. Patient outcome was similar between treatment groups and the primary and secondary endpoints were not met; progression-free survival was 4.4 versus 5.6 months and overall survival was 9.4 versus 10.7 months with cetuximab combination and control treatment, respectively. Overall response rates were 29% with cetuximab and 30% with control. Cetuximab is not listed by NCCN on p. GAST-E.

Moehler M, Galle PR, Gockel I, et al. The multidisciplinary management of gastrointestinal cancer. Multimodal treatment of gastric cancer. Best Pract Res Clin Gastroenterol. 2007;21(6):965-981.

Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol. 2007;18(3):510-517.

J.A.Chan et al, A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma

Jan Kulig et al, Targeted therapy for gastric cancer–current status J Oncol Pharm Pract (2013) 19(1): 75-81

For Erbitux in other cancers besides colon cancer, see here, here and here

For Lay version see here

Interferon for VIPoma – pro

M Levin, MD — Fri, 14 Dec 2012 16:48:17 +0000

The VIPoma syndrome is rare and difficult to treat and for this reason, ti is not well studied. It is usually caused by a neuroendocrine tumor located in the pancreas or other organs and present primarily with diarrhea. Treatment relies on resection and octreotide but occasionally interferon or steroids can be used as adjuncts (Best Practice, Eppocrates). On the other hand, other reviews do not mention interferon or mention it in combiantion with 5FU, which itself is basd on older and limited literature.
Eriksson B, Oberg KSOActa An update of the medical treatment of malignant endocrine pancreatic tumors. Oncol. 1993;32(2):203.

http://bestpractice.bmj.com/best-practice/monograph/876/treatment.html, 2012

https://online.epocrates.com/u/2942876/VIPoma/Treatment/Tx+Details

For Lay Version see here

Tykerb gastric cancer – pro

M Levin, MD — Fri, 02 Nov 2012 12:19:25 +0000

Gastric cancer is known to have amplification of the ErbB2 (HER2) gene and Herceptin is supported for use in gastric cancer. Recently, there has been an interest in using Tyker(lapatinib) which is a drug that utalizes the same mechanism of action as Herceptin. One such trial is: LOGiC – Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib. This is an international multi-center trial that will enroll patients with locally advanced, unresectable, or metastatic gastric, esophageal, or gastro-esophageal junction cancer whose tumors have amplification of the ErbB2 (HER2) gene. The trial will investigate whether lapatinib, when added to the chemotherapy regimen, capecitabine plus oxaliplatin (CapeOx), extends the time to progression and overall survival. CapeOx is administered to all patients, and patients will be randomly assigned to receive either lapatinib or placebo. There is evidence of effectiveness for brian metastases, at least in breast cancer(Lin et al).

Iqbal et al showed that Tykerb is an effective first line drug. The evidence thus far suggests that the combination of lapatinib + capecitabine shows promising efficacy and is well tolerated as 1st line treatment for advanced GC(Pishvaian et al). The same appears to be true of paclitaxel and lapatinib and studies of this combination are ongoing.

A number of issues remain to study: the type of combination therapy, the role of Taykeb in patients previousely treated with Herceptin, and efficacy in brain mets of patients with gastric cancer.

S. Iqbal et al, Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer Ann Oncol (2011) 22 (12): 2610-2615

Power, D. G., Kelsen, D. P & Shah, M. A. Advanced gastric cancer—slow but steady progress. Cancer Treat. Rev. 36, 384-392 (2010).

Ku, G. Y. & Ilson, D. H. Esophagogastric cancer: targeted agents. Cancer Treat. Rev. 36, 235-248 (2010).

Grothey, A. EGFR antibodies in colorectal cancer: where do they belong? J. Clin. Oncol. 28, 4668-4670 (2010).

M. Pishvaian, D. Sakaeva, R. K. Hsieh, S. Y. Rha, G. Caderillo-Ruiz, W. H. Miller Jr., A. M. Kemner, Y. M. Nagarwala, W. Zhang, H. Lenz; Georgetown University Medical Center, Washington, DC; Clinical Oncology Dispensary of the Republic of Bashkortostan, Ufa, Russia; Mackay Memorial Hospital, Taipei, Taiwan; Yonsei Cancer Center, Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, South Korea; Deparment of Medical Oncology, Instituto Nacional de Cancerologia, Tlalpan, Mexico; Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada; GlaxoSmithKline, Collegeville, PA; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA A global, multicenter phase II trial of lapatinib plus capecitabine in gastric cancer. J Clin Oncol 29: 2011 (suppl 4; abstr 88)

Lin NU, Diéras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roché H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009 Feb 15;15(4):1452-9.

For Lay versions see here

Taxotere/Avastin for esophageal cancer – pro

M Levin, MD — Thu, 06 Sep 2012 17:11:24 +0000

Bevacizumab, a recombinant humanized mAb, binds to all isoforms of human VEGF with high affinity and prevents the binding of VEGF to its receptor. For esophageal cancer, bevacizumab is in the early stages of clinical development. Most trials have been limited to GE adenocarcinomas, given the life-threatening hemoptysis described in bevacizumab-treated patients with squamous cell carcinoma of the lung. A multi-center phase II study of irinotecan, cisplatin, and bevacizumab in 20 patients with unresectable or metastatic gastric or GE adenocarcinoma has shown encouraging preliminary results. Shah and colleagues reported an 87% control rate (PR/SD). Of the 10 patients with measurable disease who completed at least two cycles, the investigators reported PRs in five (50%), minor PRs in four (40%), and stable disease in one. The combination therapy was well tolerated, although, as detailed in a recent update, six (25%) of 24 patients developed thromboembolic events, one patient had a gastric perforation, and another had a near perforation on imaging. There are a number of ongoing trials with various chemotherapy agents. A phase II study of Taxotere and Avastin has recently been reported in an abstract form.

Given that most patients with locally advanced esophageal cancer are treated with concurrent chemoradiation, there may also be a possible integrative role for VEGF blockade and this is being studied in clinical trials.

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

Phase II study of bevacizumab and docetaxel in metastatic esophageal and gastric cancer
Sub-category: Multidisciplinary Treatment
Category: Esophagus and Stomach
Meeting: 2006 Gastrointestinal Cancers Symposium
Abstract No: 68
Author(s): P. C. Enzinger, P. Fidias, J. Meyerhardt, K. Stuart, C. Fuchs, M. Huberman, R. Goldstein, M. Attawia, C. Lawrence, A. X. Zhu

nccn.org, esophageal cancer

TACE – pro

M Levin, MD — Thu, 06 Sep 2012 16:38:23 +0000

Chemoembolization (CE) involves the periodic injection of chemotherapy mixed with embolic material into selected branches of the hepatic arteries feeding liver tumors. CE has been successfully used as a palliative treatment of symptoms associated with functioning neuroendocrine tumors involving the liver. The most common such tumor is the carcinoid tumor whose hormone production is associated with the carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea. Pancreatic endocrine tumors that produce gastrin, insulin or other pancreatic hormones are unusual types of neuroendocrine tumors. Pancreatic endocrine (i.e., islet cell) tumors must be distinguished from the more common pancreatic epithelial tumors that arise from the exocrine portion of the pancreas.

The prognosis for patients with unresectable hepatocellular carcinoma (HCC) tumors is extremely poor. Even in the case of small nodular lesions detected by US screening, patients receiving no treatment showed a mean 3-year survival rate of 12. For unresectable, primary HCC, TACE is indicated in persons with small encapsulated nodules (less than 4 cm in diameter), no evidence of extrahepatic metastases, and with adequate hepatic (serum bilirubin concentration < 2.9 mg/dl) and renal function (serum creatinine < 2.0 mg/dl).

According to available literature, chemoembolization (TACE) may be indicated for symptomatic treatment of functional neuroendocrine cancers (i.e., carcinoid tumors and pancreatic endocrine tumors) involving the liver, in persons with adequate hepatic function (bilirubin < 2 mg/dl, absence of ascites; no portal vein occlusion; and tumor involvement of < 65 % of liver). For carcinoid tumors, TACE is indicated only in persons who have failed systemic therapy with octreotide to control carcinoid syndrome (e.g., debilitating flushing, wheezing and diarrhea).

Phase II studies of chemoembolization for metastatic colorectalcancer have been reported by several centers in the United States.Patients enrolled in these trials are usually individuals inwhom systemic and/or intraarterial infusion chemotherapy hasfailed. Abramson et al devised a spreadsheet model to determinecost-effectiveness thresholds for palliative chemoembolizationfor colorectal metastases. A mean survival time of 12 monthsor greater was demonstrated to be necessary for chemoembolizationto be considered a cost-effective method of treatment. Langet al used a combination of superselective segmental andselective lobar injections of a doxorubicin/iodized oil emulsionin the treatment of 46 patients. The actuarial survival rateswere 68% at 1 year and 37% at 2 years. In the study of Sanz-Altamiraet al 40 patients received chemoembolization with 5-fluorouracil,mitomycin-c, iodized oil, and gelatin sponge. The median survivaltime after the first chemoembolization procedure was 10 months.A number of prognostic factors predictive of longer survivalwere identified. Patients with an Eastern Cooperative OncologyGroup performance status of 0 or 1 had a median survival of24 months, versus 3 months among patients with a performancestatus of 2. Patients with extrahepatic disease at the timeof initial chemoembolization had a median survival of 3 months,versus 14 months for those with isolated liver metastases. Amongpatients with good performance status and no extrahepatic disease,the survival rates were 73% at 1 year and 61% at 2 years afterchemoembolization. In the study of Tellez et al (46), 30 patientsunderwent chemoembolization with cisplatin, doxorubicin, mitomycin-c,and bovine collagen. Median survival times were 8.6 months fromfirst chemoembolization and 29 months from diagnosis. In a studyby Soulen (47), 51 patients underwent chemoembolization withcisplatin, doxorubicin, mitomycin-c, iodized oil, and polyvinylalcohol. Actuarial survival rates from diagnosis with livermetastases were 86%, 55%, and 23% at 1, 2, and 3 years, witha median of 24 months. Outcomes in patients with isolated livermetastases who were treated with chemoembolization by Salmanet al were similarly encouraging, with a mean survivaltime of 15 months versus 8 months among patients with extrahepaticdisease. The results in these extensively pretreated patientsare promising, but high early response rates do not necessarilycause an improvement in survival. A consistent trend towardsurvival times longer than 12 months after initial therapy hasalso been demonstrated, suggesting that chemoembolization forcolorectal metastases is a cost-effective method of treatmentfor patients with good performance status and disease isolatedto the liver. To best determine absolute survival benefit, amulticenter phase II/III trial was initiated by the AmericanCollege of Radiology Imaging Network. The purpose of the trialwas to compare outcomes with chemoembolization combined withsystemic therapy versus systemic therapy alone. This trial was stopped because of the evolution of new agents and the resultantparadigm shift regarding the standard of systemic therapy. NCCN recommends arterialy directed therapies, which includes chemoembolization.

Absolute contraindications for TACE in patients with unresectable HCC include intractable systemic infection, Child –Pugh C, or the presence of hepatofugal portal flow. Other traditional contraindications include significant cardiac or renal failure, severely impaired liver function, clinically relevant ascites, significant thrombocytopenia, portal vein thrombosis, or patients with a transjugular intrahepatic portosystemic shunt (Maleux 2009).

Relative contraindications include a variety of other factors including, but not limited to: Serum bilirubin >2 mg/dL, Lactate dehydrogenase >425 unit/L, Aspartate aminotransferase >100 unit/L, Tumor burden involving >50 percent of the liver, Cardiac or renal insufficiency, acites, recent variceal bleed, or significant thrombocytopenia.

Transarterial chemoembolization (TACE) of the liver is generally not considered medically necessary for the treatment of liver metastases from other non-neuroendocrine primaries, including colorectal cancer, melanoma, and unknown primaries. The use of TACE in liver mets, of cancers other than neuroendocrine is not supported by credible literature to prolong survival and it is still being studied.

Brown DB, Cardella JF, Sacks D, Goldberg SN, Gervais DA, Rajan DK, Vedantham S, Miller DL, Brountzos EN, Grassi CJ, Towbin RB, SIR Standards of Practice Committee. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol 2009 Jul;20(7 Suppl):S219-S226, S226.e1-10. [71 references]

Riccardo Lencioni New Perspectives in Hepatocellular Cancer Seminars in Oncology Volume 39, Issue 4, August 2012, Pages 503–509

Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol. 2002;13(9 Pt 2):S211-S221.
Oliveri RS, Gluud C. Transcatheter arterial embolisation and chemoembolisation for hepatocellular carcinoma (Protocol for Cochrane Review). Cochrane Database Systematic Rev. 2004;2:CD004787.

D. B. Brown, J.-F. H. Geschwind, M. C. Soulen, S. F. Millward, and D. Sacks
Society of interventional radiology position statement on chemoembolization of hepatic malignancies.
J. Vasc. Interv. Radiol., February 1, 2006; 17(2): 217 – 223.

Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37(2):429-442.

Gaba RC. Chemoembolization practice patterns and technical methods among interventional radiologists: results of an online survey. AJR Am J Roentgenol. 2012 Mar;198(3):692-9.

Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology. 2002;224(1):47-54.

Maleux G, van Malenstein H, Vandecaveye V, Heye S, Vaninbroukx J, Nevens F, Verslype C. · Department of Radiology, University Hospitals Leuven, Leuven, Belgium. · Dig Dis. ·Article Transcatheter chemoembolization of unresectable hepatocellular carcinoma: current knowledge and future directions. 2009 Pubmed #19546554

Cisplatin/irinotecan for Gastric Cancer – pro

M Levin, MD — Thu, 06 Sep 2012 16:36:44 +0000

Both irinotecan and cisplatin are considered standard agents for stomach cancer and NCCN recommends cisplatin or irinotecan based regimens. Cisplatin has been a popular drug for this disease for 2 decades. Recent data have emerged on the use of irinotecan in advanced gastric cancer, both as a single agent and in various combination regimens. Active irinotecan-based combinations include cisplatin–irinotecan, 5-FU–LV–irinotecan, and irinotecan–oxaliplatin. These combinations have produced acceptable response rates and overall survival times but have also been associated with significant grade 3–4 neutropenia and diarrhea. Diarrhea is the major dose-limiting toxicity of irinotecan therapy and occurred in approximately 20% of patients (range, 6%–27%). Overall, results of these trials indicate that these irinotecan combinations are clinically active, justifying the NCCN recommendation.

There is significant support from phase II studies and one second line study versus observation to conclude that single agent irinotecan is medically necessary when a combination cannot be administered.

P. C. Thuss-Patience, A. Kretzschmar, T. Deist, A. Hinke, D. Bichev, B. Lebedinzew, G. Schumacher, B. Gebauer, V. Maier, P. Reichardt; Charité-Universitätsmedizin Berlin, Campus-Virchow-Klinikum, Berlin, Germany; HELIOS Klinikum Berlin-Buch, Berlin, Germany; Kreisklinik Aschersleben-Staßfurt, Aschersleben, Germany; WiSP Research Institute, Langenfeld, Germany; HELIOS Klinikum Bad Saarow, Bad Saarow, Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Germany J Clin Oncol 27:15s, 2009 (suppl; abstr 4540)

http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf

J. A. Ajani Evolving Chemotherapy for Advanced Gastric Cancer
Oncologist, October 1, 2005; 10(suppl_3): 49 – 58.

Narikazu Boku, Atsushi Ohtsu, Yasuhiro Shimada, Kuniaki Shirao, Shigeki Seki, Hiroshi Saito, Yuh Sakata, Ichinosuke Hyodo, Phase II Study of a Combination of Irinotecan and Cisplatin Against Metastatic Gastric Cancer Journal of Clinical Oncology, Vol 17, Issue 1 (January), 1999: 319

HAI for hepatic mets – pro

M Levin, MD — Thu, 06 Sep 2012 16:35:41 +0000

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared to systemic chemotherapy.Controversy regarding the efficacy of regional chemotherapy has led to initiation of a large multicenter phase III trial (CLB-9481) of hepatic arterial infusion versus systemic chemotherapy. The use of the combination of intra-arterial chemotherapy with hepatic radiation therapy, especially employing focal radiation of metastatic lesions, is under evaluation. Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis. Several randomized trials of HAI therapy in patients with unresectable liver metastases from CRC have demonstrated higher response rates and longer TTHP than those seen with systemic fluoropyrimidine-based chemotherapy. Analysis of survival benefits is limited by methodological flaws, technical problems, and high toxicity in early studies; however, a recent CALGB multicenter study demonstrated an overall survival benefit for HAI of FUDR and dexamethasone versus systemic 5-FU and LV.

A great deal of progress has been made in the regional treatment of CRC liver metastases since the introduction of HAI chemotherapy over 40 years ago. Improvement in surgical techniques and the development of implantable pumps have decreased technical complications and improved patient tolerability of treatment. Whether this benefit will hold up in comparison with more active systemic regimens using irinotecan or oxaliplatin is unknown.

The use of HAI of FUDR and systemic 5-FU/LV following resection of hepatic metastases clearly decreases local recurrence and can improve 2-year survival, and further study of HAI in this setting is warranted. Both hepatic and extrahepatic relapses remain a problem and, therefore, initial studies combining HAI with newer systemic agents, such as irinotecan and oxaliplatin, are under way. These should provide a framework to guide us as to which combination regimens are the most effective and well-tolerated. Ultimately, this should lead to randomized trials of HAI therapy plus systemic chemotherapy versus our most active systemic chemotherapy alone in order to determine the best approach to treating hepatic CRC metastases.

The real question is whether these studies apply to HAI versus new multi-drug therapies, which are much more effective.
Anotehr question is whether systemic therapy Is necessary in addition to intraarterial therapy. It is also not known whetehr drugs such as cisplatin mitomycin work better than FUDR – this has not been tested. Experts remain in conflict but NCCN does recommend HAI.

Chari et al, Chemotherapy and Regional Therapy of Hepatic Colorectal Metastases: Expert Consensus Ann Surg Oncol.2006; 13: 1293-1295

Other expert opinions:

Chemotherapy and Regional Therapy of Hepatic Colorectal Metastases: Expert Consensus Statement
David L. Bartlett, Jordan Berlin, Gregory Y. Lauwers, Wells A. Messersmith, Nicholas J. Petrelli, and Alan P. Venook
Annals of Surgical Oncology Oct 1 2006: 1284-1292.

Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement
Chusilp Charnsangavej, Bryan Clary, Yuman Fong, Axel Grothey, Timothy M. Pawlik, and Michael A. Choti
Annals of Surgical Oncology Oct 1 2006: 1261-1268.

Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement by Charnsangavej et al.
William C. Chapman, Paulo M. Hoff, and Steven M. Strasberg
Annals of Surgical Oncology Oct 1 2006: 1269-1270.

Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement By Abdalla et al.
Reid B. Adams, Daniel G. Haller, and Mark S. Roh
Annals of Surgical Oncology Oct 1 2006: 1281-1283.

Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement
Eddie K. Abdalla, René Adam, Anton J. Bilchik, Daniel Jaeck, Jean-Nicolas Vauthey, and David Mahvi
Annals of Surgical Oncology Oct 1 2006: 1271-1280

Unresectable Hepatic Colorectal Metastases: Need for New Surgical Strategies
Jean-Nicolas Vauthey and Eddie K. Abdalla
Annals of Surgical Oncology Jan 1 2006: 5-6.

Alice C. Wei, Paul D. Greig, David Grant, Bryce Taylor, Bernard Langer, and Steven Gallinger Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience Annals of Surgical Oncology May 1 2006: 668-676.

NCCN.ORG, Colon Cancer

Chemo for metastatic esophageal cancer – pro

M Levin, MD — Thu, 06 Sep 2012 16:34:30 +0000

Lay Summary: Metastatic esophageal cancer is often treated with chemotherapy. Drugs with the most supporting evidence for effectiveness are: cisplatin, 5-fluorouracil (5-FU), paclitaxel and antracyclins. How to best combine them with each other and novel agents is being studied.

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 assoletherapy 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 beenshort livedand 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 andantracyclins. Combiningtaxotereand Xeloda is not supported bysignificantliterature.

Keytruda is listed by NCCN as ”Useful in certain circumstances:, but not for PDL-1 positive cancers but for MSI-H, dMMR or TMB high. In the section “Esophageal and Esophagogastric Junciton Cnaers”, it does list PDL-1. The FDA has approved pembrolizumab (Keytruda) for use in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal carcinoma who are ineligible for surgical resection or definitive chemoradiation.

Conroy, Y. Yataghene, P. L. Etienne, P. Michel, H. Senellart, J. L. Raoul, L. Mineur, M. Rives, X. Mirabel, A. Adenis Definitive chemo-radiotherapy (CRT) with folfox 4 or 5FU-cisplatin as first line treatment for patients (pts) with inoperable esophageal cancer (IEC): Final results of a randomized phase II study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4532

M. Stahl, C. Mariette, K. Haustermans, A. Cervantes, D. Arnold, Oesophageal Cancer: ESMO Clinical Practice Guidelines Ann Oncol 2013; 24 (Suppl 6): vi51-vi56.

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.

M. Koshy, N. Esiashvilli, J. C. Landry, C. R. Thomas Jr., and R. H. Matthews Multiple Management Modalities in Esophageal Cancer: Combined Modality Management Approaches Oncologist, April 1, 2004; 9(2): 147 – 159.

NCCN.ORG, Esophageal Cancer 2020

NCCN Esophageal 2022, ESOPH-F, 4

Chemo for HCC – pro

M Levin, MD — Thu, 06 Sep 2012 16:32:19 +0000

The only proven potentially curative therapy for HCC remainssurgical, either hepatic resection or liver transplantation,and patients with single small HCC ( 5 cm) or up to three lesions3 cm should be referred for assessment for these treatment modalities. A variety of local therapies are avialble short of surgical resection. In regard to chemotherapy, palliative systemic therapy with doxorubicin (Adriamycin) has been considered a standard of therapy with response rates of 10 to 20 % with usually partial responses, but with no evidence for survival benefit. As doxorubicin is metabolized by the liver, the dose needs to be reduced or discontinued with rising bilirubin levels and liver dysfunction. Single agent 5-flurouracil, capecitabine or gemcitabine may be better tolerated in such a situation but still with low objective response rates. Combination chemotherapy regimens results in higher response rates but at increased toxicities and unproven survival benefits, and are not usually recommended.

Combination chemotherapy produces better results in HCC. Cisplatin (CDDP)-containing regimens such as epirubicin, 5-FU and CDDP produces a response rate of up to 25% a regimen comprising gemcitabine and CDDP produces a response rate of 21%. However, median survivals were still short. A National Cancer Centre clinical study is evaluating gemcitabine and CDDP. More recently, a French Phase II study reported 19% response rate and 48% stable disease to combination gemcitabine and oxaliplatin. One compelling Hong Kong study with CDDP, interferon-alpha (IFN- a ), doxorubicin, and infusional 5-FU (PIAF), a modification of an MD Anderson regimen, reported a response rate of 26% in advanced HCC and pathologic complete response in 44% of HCC patients who were able to undergo surgical resection following chemoimmunotherapy cytoreduction. The overall median survival was 8.9 months. It was also shown that normalization of tumour marker alphafetoprotein ( a FP) was predictive of pathologic complete remission in these HCC patients. This illustrates that radiological response evaluation may underestimate the true response. Toxicity was a problem in this intensive regimen with a 4% mortality and significant morbidity. Combinations of 5-FU with IFN- a have divergent results with one study reporting responses in 9 of 36 HCC patients. The role of single agent IFN- a against HCC may be related to its anti-angiogenesis mechanism, its ability to induce anti-tumour immunity or both, but clinical studies have again ranged from zero response rates to studies suggesting response rates better than doxorubicin with a survival benefit. Newer agents such as bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), or Thalidomide (an immune modifier or angiogenesis inhibitor) used alone or in combination with chemotherapy remain experimental. New combinations such as capecitabine and avastin (an antibody against vascular endothelial growth factor), the focus of an ongoing Asia-Pacific study, are promising, not least for its ability to produce low toxicity and potentially target this highly vascular tumour. However, they remain experimental and intriasl at this time.

A recent guideline states: “Systemic chemotherapy with standardagents has a poor responserate and should only be offered inthe context of trials ofnovel agents (evidence grade I, recommendationgrade A).^“NCCN only recommends chemotherapy in a context of clinical

^{trial (p.9).}

S D Ryder Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults Gut 2003;52:iii1

Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005 Nov;42(5):1208-36. [322 references]

Xelox + Avastin for metastatic CRC – pro

M Levin, MD — Thu, 06 Sep 2012 16:26:44 +0000

Avastin has been shown to be more effective with Folfox than Folfox alone. Preliminary results from a large, randomized clinical trial for patients with advanced colorectal cancer who had previously received treatment show that those who received bevacizumab (Avastin™) in combination with an oxaliplatin (Eloxatin™) regimen known as FOLFOX4 lived longer than patients who received FOLFOX4 alone.

The Data Monitoring Committee overseeing the trial (known as E3200)* recommended that the results of a recent interim analysis be made public because the study had met its primary endpoint of demonstrating improved overall survival. Researchers found that the patients in the trial who received bevacizumab in combination with FOLFOX4 (a regimen of oxaliplatin, 5-fluorouracil and leucovorin) had a median overall survival of 12.5 months compared to patients treated with FOLFOX4 alone, who had a median overall survival of 10.7 months. This difference is statistically significant and corresponds to a 17 percent improvement in median overall survival. There was a 26 percent reduction in the risk of death (hazard ratio of 0.74) for patients in this study who received bevacizumab plus FOLFOX4 compared to those who received FOLFOX4 alone.

The plan resricts Avastin for colorectal cancer to 5FU based regimens, in accordance with the FDA indication. Xeloda is generally considered to be eqivalent to 5Fu and it is a 5FU pro-drug. A number of studies suggest that it is as effective as Folfox. A Phase III study showed the chemotherapy combination XELOX (Xeloda + oxaliplatin) to be as effective — in terms of progression-free survival (PFS) — as the current standard treatment, FOLFOX-4 (infused 5-FU/leucovorin + oxaliplatin), in the treatment of advanced (metastatic) colorectal cancer. However, a Phase III trial NCT00349336 is currenlty looking at this question. This study will compare the pharmacokinetics and safety of Avastin at steady state under 2 different dosing regimens, in combination with XELOX (oxaliplatin + Xeloda) or FOLFOX-4 (oxaliplatin, leucovorin and 5-fluorouracil). Patients randomized to the XELOX arm will receive Avastin (7.5mg/kg iv) on Day 1 of each 3 week cycle; patients randomized to the FOLFOX-4 arm will receive Avastin (5mg/kg iv) on Day 1 of each 2 week cycle. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-42.

nccn.org, Colorectal cancer

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