Cancer Treatment

Tykerb for gastric cancer

22% of patients with advanced gastric cancer overexpress human epidermal growth-factor receptor 2 (HER2), and these patients had significantly improved overall survival when trastuzumab (Herceptin) is added to chemotherapy, compared with chemotherapy alone. In a study presented in 2009 ASCO, the improvement in overall survival was 2.7 months, from 11.1 months in the chemotherapy group to 13.8 months in the trastuzumab group (hazard ratio, 0.74, P = .0046).  SImilar results were shown by ToGA, a large international Phase III trial investigating the benefit of Herceptin as the first therapy for patients with advanced and inoperable stomach cancer (first line).
This greatly increased and interest in Tykerb for gastric cancer. Preclinical studies in gastric cancer have shown that the drug has concentration-dependant antiproliferative properties against HER2-positive gastric cancer cell lines, showing synergy with trastuzumab.This agent is under study alone and combinations. A recent study by Iqbal concluded that Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients.

There are several ongoing studies of Tykerb and gastric cancer, for example: 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, NCT00680901. There is also the TYTAN trials investigating weekly paclitaxel plus or minus lapatinib in second-line therapy.

 

 

Van Cutsem E, Kang Y, Chung H et al. Efficacy results from the ToGA trial: a Phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Presented at the 2009 annual meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. Abstract LBA4509.

Y. Kang, Y. Bang, F. Lordick, S. Park, A. Sawaki, H. Chung, L. Shen, J. M. Xu, J. Leon-Chong, E. Van Cutsem Incidence of gastric and gastro-esophageal cancer in the ToGA trial: Correlation with HER2 positivity 2008 Gastrointestinal Cancers Symposium , Ab. 11

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)
doi: 10.1093/annonc/mdr021

 

C-MET as target for GE Junction cancer

Since GE Junctions cacners that express HER respond well to Herceptin, there is great interest in targeting molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways. Much remians to be done before clinical therapies based on this concept become available and proven. One study looking at a C-MET inhibitor is: MET111643 ,A Phase 2 Study of GSK1363089 (XL880) Administered Orally to Subjects with Metastatic Gastric Cancer.

Jochen K. Lennerz, Eunice L. Kwak, Allison Ackerman, Michael Michael, Stephen B. Fox, Kristin Bergethon, Gregory Y. Lauwers, James G. Christensen, Keith D. Wilner, Daniel MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib, JCO VOLUME 29
NUMBER 36
DECEMBER 20 2011

Ajani JA: Gastroesophageal cancers: Progress and problems. J Natl Compr Canc Netw 6:813-814, 2008

nccn.org, Gastric cancer 2012

 

Xeloda alone for gastric cancer

5FU has been used in gastric cancer for decades. Xeloda has been found able to subtitute for 5FU in other cancer types. It is now usually used with cisplatin, oxaliplatin or with epirubicin based regimen. 

Going back to older studies of Xeloda for gastric cancer, we find that it is effective as a single agent. Phase I studies of capecitabine in various dose and administration regimens were used to test its safety, tolerability and pharmacokinetics. The recommended Phase II dose of capecitabine was set at 2510 mg/m2/day. Other Phase I trials used continuous daily dosing or a 3-weekly intermittent regimen with leucovorin. 

The efficacy and safety of 3-week intermittent capecitabine monotherapy was tested in a Korean study that included 44 chemonaive patients. The ORR was 34%, with a median TTP of 3.2 months. While this 3-week inter-mittent schedule has been adopted as the global standard, a 4-week on-and-off schedule has been evaluated in Japan. In these studies, the ORRs were 19.4-26%, the median OS was 8.2-10.0 months and the toxicity profiles were highly favorable. A randomized Phase II study of the 3-week capecitabine regimen was also evaluated in elderly patients; the ORR was 27% with a median TTP of 4.7 months, and the toxicity profile was favorable.

I am not aware of other definitive studies of single agent Xeloda. Uptodate provides a level 2B recommendation for Xeloda in elderly patients with metastatic gastric cancer. However, NCCN on p. 14 does not cite Xeloda.

Koizumi W, Saigenji K, Ujiie S, Terashima M, Sakata Y, Taguchi T: A pilot Phase II study of capecitabine in advanced or recurrent gastric cancer. Oncology 64(3), 232-236 (2003).

Sakamoto J, Chin K, Kondo K et al.: Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer. Anticancer Drugs 17(2), 231-236 (2006).

Kang Y, Lee J, Min Y et al.: A randomized multi-center Phase II trial of capecitabine (X) versus S-1 (S) as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. J. Clin. Oncol. (Meeting Abstracts) 25(Suppl. 18), 4546 (2007).

Herceptin for gastric cancer

Many insurers now cover gastric cancer as an appropriate indication under policy for Herceptin therapy, provided that it is HER 3+  by IHC of by FISH, that a cardiac workup was carried out and that it is used in one line of therapy. 22% of patients with advanced gastric cancer overexpress human epidermal growth-factor receptor 2 (HER2), and these patients had significantly improved overall survival when trastuzumab (Herceptin) is added to chemotherapy, compared with chemotherapy alone. In a study presented in 2009 ASCO, the improvement in overall survival was 2.7 months, from 11.1 months in the chemotherapy group to 13.8 months in the trastuzumab group (hazard ratio, 0.74, P = .0046).  SImilar results were shown by ToGA, a large international Phase III trial investigating the benefit of Herceptin as the first therapy for patients with advanced and inoperable stomach cancer (first line).
This would include gastroesophageal junction cancer, which  preliminary results for ToGa show is highly HER+. There are currently no open studies on clinicaltrials.gov of Herceptin for esophageal cancer.

Van Cutsem E, Kang Y, Chung H et al. Efficacy results from the ToGA trial: a Phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Presented at the 2009 annual meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. Abstract LBA4509.

Y. Kang, Y. Bang, F. Lordick, S. Park, A. Sawaki, H. Chung, L. Shen, J. M. Xu, J. Leon-Chong, E. Van Cutsem Incidence of gastric and gastro-esophageal cancer in the ToGA trial: Correlation with HER2 positivity 2008 Gastrointestinal Cancers Symposium , Ab. 11

IMRT for gastric cancer

Compared with the conformal plans, oncologists frequently preferred IMRT plans when using dose-volume histogram data. The advantages of IMRT plans include both improved planning target volume coverage and improved sparing of critical organs.However, organ motion during breathing is a problem for IMRT planning and accuracy. A recent study found that: "When compared with either AP/PA or 3-field plans, IMRT significantly reduced the volume exceeding the threshold dose of the liver and at least one kidney. Target coverage with IMRT was excellent, with 98±1% of the target receiving 100% of the dose. Compared with AP/PA and 3-field plans, IMRT plans had a greater percentage of target receiving the prescribed dose, but also a greater volume receiving >110% of the dose." It concluded tha more study is needed: "In summary, IMRT offers improved sparing of normal structures, allowing a dose of 50.4 Gy to be delivered to the PTV. In this small series of patients, treatment was well tolerated with acceptable toxicity, seemingly improved as compared with the Intergroup trial. IMRT in the treatment of gastric cancer warrants further study."

Milano, M T, Garofalo, M C, Chmura, S J, Farrey, K, Rash, C, Heimann, R, Jani, A B
Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques
Br J Radiol 2006 79: 497-503

Petra Wieland et al, IMRT for postoperative treatment of gastric cancer: covering large target volumes in the upper abdomen: a comparison of a step-and-shoot and an arc therapy approach, International Journal of Radiation Oncology*Biology*Physics
Volume 59, Issue 4, 15 July 2004, Pages 1236-1244   

Adjuvant Gleevec for GIST

Preliminary results from a large, randomized, placebo-controlled clinical trial for patients with primary gastrointestinal stromal tumor (GIST), a type of tumor usually found in the stomach or small intestine, showed that patients who received imatinib mesylate (Gleevec ®) after complete removal of their tumor were significantly less likely to have a recurrence of their cancer compared to those who did not receive imatinib. In this study, Gleevec was given for one year. It is now more than a year after resection of all disease.  Most recent ASCO GI 2008 update suggested that recurrences are greater about a year and a half after Gleevec is stopped but this cannot be used to allow GLeevec indefinitely without additional studies. Paolo Casali, M.D., of the National Tumor Institute in Milan, Italy, cautioned that, although the trial had extensive follow-up, it was still a small trial. He said European researchers don't believe the findings are sufficient to recommend adjuvant imatinib

PET for gastric cancer

Positron emission tomography using 2-deoxy-2-[18F] fluorodeoxyglucose (FDG-PET) has been used to detect malignancies associated with certain kinds of tumors. Data regarding the use of FDG-PET scan for evaluating gastric cancer are scarce. A recent review of studies showed that PET produced an estimated 14% change was noted in management effect, based on 109 patient studies for diagnosis/staging in gastric cancer; however, this is no randomized data.
Several Western guidelines state that PET is not routinely indicated for gastric cancer. This refers to both staging and restaging. Japanese literature (where this cancer is very common) is more suggestive that it may be useful in preoperative staging of lymph nodes (in Japan a wider lymph node dissection is performed than in the West) but it does not contain the same recommendations for PET for restaging. A recent review paper says: "POSITRON-EMISSION TOMOGRAPHY (PET) for these assessments may be useful although currently available data are limited." NCCN sys that PET is optional for staging.

 

Table of studies: http://www.petscaninfo.com/zportal/portals/phys/clinical/jnmpetlit/index_html/JNM_OncoApps/JNM_Table10/article_elements_view

http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf, p.5

Analysis Ken Herrmann, Katja Ott, Andreas K. Buck, Florian Lordick, Dirk Wilhelm, Michael Souvatzoglou, Karen Becker, Tibor Schuster, Hans-Jürgen Wester, Jörg R. Siewert, Markus Schwaiger, and Bernd J. KrauseImaging Gastric Cancer with PET and the Radiotracers 18F-FLT and 18F-FDG: A Comparative  J Nucl Med 48: 1945-1950; First published on November 15, 2007;

 

Kota Mukai et al Usefulness of preoperative FDG-PET for detection of gastric cancer
Journal Gastric Cancer Volume 9, Number 3 / August, 2006

Chen, J, Cheong, JH, Yun, MJ, Kim, J, Lim, JS, Hyung, WJ  et al.  (2005) "Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography" Cancer 103: 2383-90

Scottish Intercollegiate Guidelines Network (SIGN). Management of oesophageal and gastric cancer. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2006 Jun. 69 p. (SIGN publication; no. 87). [393 references]

Dimitrios H Roukos and Angelos M Kappas Perspectives in the treatment of gastric cancerNature Clinical Practice Oncology (2005) 2, 98-107

Followup of resected gastric cancer

Patients with early gastric cancer have an excellent prognosis after appropriate treatment, with a high survival rate and a low rate of recurrence.There are no guidelines as to how to follow gastric cancer. A recent review concluded: " Early detection of asymptomatic gastric cancer recurrence did not improve overall survival of patients with recurrence after curative resection. Until development of more effective treatment for this disease, close follow-up may offer no survival benefit. " After 5 years, it is usually assumed that a cancer is cured and the proposed intensive re-evalaution in not supported by credible literature.It is still unclear whether intensive follow-up after surgery produces significant benefits in patients with gastric cancer. A previous retrospective study concluded that follow-ups were not useful.There have been no data to suggest that chemotherapeutic agents are useful in the treatment of recurrent gastric cancer detected during follow-up.

C. Kunisaki, H. Akiyama, M. Nomura, G. Matsuda, Y. Otsuka, H. Ono, Y. Nagahori, H. Hosoi, M. Takahashi, F. Kito, et al.
Significance of Long-Term Follow-Up of Early Gastric Cancer
Ann. Surg. Oncol., March 1, 2006; 13(3): 363 - 369.

Yasuhiro Kodera, MD, Seiji Ito, MD, Yoshitaka Yamamura, MD, Yoshinari Mochizuki, MD, Michitaka Fujiwara, MD, Kenji Hibi, MD, Katsuki Ito, MD, Seiji Akiyama, MD and Akimasa Nakao, Follow-Up Surveillance for Recurrence After Curative Gastric Cancer Surgery Lacks Survival Benefit Annals of Surgical Oncology 10:898-902 (2003)

Kodera Y, Ito S, Yamamura Y, et al. A follow-up surveillance for recurrence after curative gastric cancer surgery lacks survival benefit. Ann Surg Oncol 2003; 10:898–902.[

Oxaliplatin and Xeloda combinations for gastric cancer

 

Epirubicin-cisplatin-5-fluorouracil (ECF) is commonly used to treat advanced gastric cancer. Two new cytotoxic agents: the platinum, oxaliplatin, and the oral fluoropyrimidine, capecitabine, have the potential to replace the cisplatin and 5-fluorouracil (5-FU) components of ECF, respectively. In this case, the regimen is capecitabine, Oxaliplatin and epirubicin.

Oxaliplatin combinations are now standard therapy for gastric cancer. Oxaliplatin based therapy is one of the options listed by NCCN for metastatic gastric cancer. The various oxaliplatin regimens in used has been extensively studied in Phase II; there are also studies with capecitabine and oxaliplatin. The 5FU.Leukovorin/oxaliplatin combination is approved by Cancer Care of Ontario which has issued evidence based recommendations and a guideline to support it (at http://www.cancercare.on.ca/pdf/pebc2-22s.pdf).  Xeloda has been found able to substitute for 5FU in other cancer types. In the REAL-2 trial presented at ASCO 2006, the central research question was whether capecitabine, an oral pro-drug, could replace protracted venous infusion 5-FU, and whether oxaliplatin could replace cisplatin in the treatment of patients with advanced/non-resectable oesophago-gastric cancers. The use of capecitabine would remove the requirement for central venous access, and the potential line-related complications and morbidity therein. Moreover, oxaliplatin has a different toxicity profile to cisplatin, and is notably less nephro- and oto-toxic. The REAL-2 study of 1,002 patients with gastroesophageal cancer had a two-by-two factorial design, comprised four treatment arms with ECF as the reference arm and was designed to demonstrate non-inferiority of capecitabine over 5-FU, and oxaliplatin over cisplatin in the perprotocol population. Approximately 40% of patients had gastric cancer. There were no significant differences in quality of life between the arms.

Xelox with epirubicin in currenlty in a randomized phase II trial: Epirubicin, Oxaliplatin, and Capecitabine or Docetaxel and Oxaliplatin in Treating Patients With Advanced Esophageal Cancer, Gastroesophageal Junction Cancer, or Stomach Cancer,NCT00806949. Thus far, the only published study is an abstract from 2008 that concludes: "A combination of epirubicin, capecitabine and oxaliplatin every third week is a highly active and convenient regimen with a favourable safety profile." However, also recently a four arm trial, one of which was the epirubicin, Xeloda and Oxaliplatin arm, showed equal efficacy with other standard arms.

NCCN has not incorporated this regimen but it does list Oxaliplatin with 5 floropyrimidines, not including epirubicin. 

NCCN has not incorporated this regimen but it does list Oxaliplatin with 5 floropyrimidines, not including epirubicin. It also says in the SOPH-E, 1 and GAST-E,1 that Cisplatin can be exchanged with oxaliplatin and Xeloda with 5-FU, but says, however, that three drug regimens  should be reserved for a medically fit adenocarcinoma patients with good performance status and ability to do frequent toxicity assessments. It, therefore, supports the Xeloda/oxaliplatin regimen.

 

 

Cunningham, David, Starling, Naureen, Rao, Sheela, Iveson, Timothy, Nicolson, Marianne, Coxon, Fareeda, Middleton, Gary, Daniel, Francis, Oates, Jacqueline, Norman, Andrew Richard, the Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom,
Capecitabine and Oxaliplatin for Advanced Esophagogastric Cancer
N Engl J Med 2008 358: 36-46

Annamaria Ruzzo, Francesco Graziano, Kazuyuki Kawakami, Go Watanabe, Daniele Santini, Vincenzo Catalano, Renato Bisonni, Emanuele Canestrari, Rita Ficarelli, Ettore Tito Menichetti, Davide Mari, Enrica Testa, Rosarita Silva, Bruno Vincenzi, Paolo Giordani, Stefano Cascinu, Lucio Giustini, Giuseppe Tonini, Mauro Magnani  Pharmacogenetic Profiling and Clinical Outcome of Patients With Advanced Gastric Cancer Treated With Palliative Chemotherapy Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1883-1891

Cunningham D, Rao S, Starling N, et al.,“Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer:The REAL 2 trial”, J Clin Oncol 2006 ASCO Annual Meeting Proceedings (2006);24: Abstract LBA4017.

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

J. S. Macdonald Gastric cancer--new therapeutic options.
N. Engl. J. Med., July 6, 2006; 355(1): 76 - 77

M. H. Kulke The Treatment of Advanced Gastric Cancer: In Search of the Right Combination
J. Clin. Oncol., July 14, 2000; 18(14): 2645 - 2647.

C. Louvet, T. Andre, J.M. Tigaud, E. Gamelin, J.Y. Douillard, R. Brunet, E. Francois, J.H. Jacob, D. Levoir, A. Taamma, P. Rougier, E. Cvitkovic, and A. de Gramont Phase II Study of Oxaliplatin, Fluorouracil, and Folinic Acid in Locally Advanced or Metastatic Gastric Cancer Patients
J. Clin. Oncol., December 1, 2002; 20(23): 4543 - 4548

E. Al-Batran, A. Atmaca, S. Hegewisch-Becker, D. Jaeger, S. Hahnfeld, M. J Rummel, G. Seipelt, A. Rost, J. Orth, A. Knuth, and E. Jaeger
Phase II Trial of Biweekly Infusional Fluorouracil, Folinic Acid, and Oxaliplatin in Patients With Advanced Gastric Cancer
J. Clin. Oncol., February 15, 2004; 22(4): 658 - 663. 6

First-line EXE (epirubicin, capecitabine, and oxaliplatin) is a highly active and convenient out-patient regimen in patients with nonresectable gastric cancer.
 2008 Gastrointestinal Cancers Symposium , 47

PET scan for GIST

PET is often used for staging and monitoring of response for GIST tumors. A recent consensus statement says: “The panelists agreed that currently available imaging techniques to evaluate GIST include computed tomography (CT), magnetic resonance imaging (MRI) and fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET). "

The journal Applied Radiology (vol. 34, no. 6, 2005), in an article titled 'Role of Positron Emission Tomographic Imaging in Gastrointestinal Stromal Tumors,' cited case studies where PET 'helped in accurate re-staging by indicating the malignant nature of the hepatic and subhepatic masses and excluding pelvic spread.' The article also noted that, 'when compared with CT alone, PET with FDG and PET/CT provided valuable additional information about the extent and metabolic activity of the disease process. … The advantage of PET lies in its ability to differentiate active tumor from a nonviable necrotic tumor mass, malignant from benign tissue, and recurrent tumor from scar tissue.'   Unfortunately, however, there is little support for EPT in GIST beyond case reports and studies.

The NCCN guidelines for soft tissue sarcoma say that  'CT can be ambiguous, but PET is more definitive' in assessing response to therapy and in determining progression. However, soft tissue sarcoma is a different condition than GIST. The aforementioned consensus statement concluded: " Evaluation of FDG uptake using PET scanning is recommended when an early detection of tumor response to imatinib treatment is required, e.g. for consideration of surgery after imatinib cytoreduction in rectal tumors (SOR expert opinion, NCCN level 2A). PET scan may also be useful in case of equivocal images suspected to be metastatic. Aside from these cases, PET scan is not mandatory in all GIST patients after complete resection (SOR expert agreement, NCCN level 2A). "

Thus, while I would approve CT or PET for staging, I would not do so for monitoring of therapy response as being medically necessary, unless a surgical decision is pending.

Consensus meeting for the management of gastrointestinal stromal tumors, Annals of Oncology 2005, Vol. 16, No. 4: 566-578.

Van den Abbeele AD, Badawi RD, Cliche JP et al. 18F-FDG-PET predicts response to imatinib mesylate (Gleevec) in patients with advanced gastrointestinal stromal tumors (GIST). Proc Am Soc Clin Oncol 2002; 21: 403a (Abstr 1610).

Stroobants S, Goeminne J, Seegers M et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Imatinib). Eur J Cancer 2003; 39: 2012–2020.

Antoch G, Kanja J, Bauer S et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004; 45: 357–365.

Choi H, Macapinlac H, Burgess M et al. Correlation of computerized tomography (CT) and proton emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Proc Am Soc Clin Oncol 2003; 22: 819.