Cancer Treatment

Adjuvant chemotherapy and radiation for ampullary cancer

Carcinoma of the ampulla of Vater is defined as a malignant tumor arising in the last centimeter of the common bile duct where it passes through the wall of the duodenum and ampullary papilla. The pancreatic duct (of Wirsung) and common bile duct merge and exit by way of the ampulla into the duodenum. The ductal epithelium in these areas is columnar and resembles that of the lower common bile duct. Adenocarcinoma of the ampulla of Vater is a relatively uncommon tumor that accounts for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas.When possible, resection is the best treatment. Because local and systemic failures remain problematic, physicians continue to be interested in offering adjuvant therapy. The relative rarity of this disease limits research in this area.

There are many small studies and retrospective reviews that suggest that adjuvant chemoradiation may improve suvival. It is not likely that prospective comparative studies will be performed in this rare disease. A 2008 guidelines says: "As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment."

Furuse J, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino M, Kondo S, Saito H, Tsuyuguchi T, Hirata K, Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Amano H, Miura F
Guidelines for chemotherapy of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg. 2008;15(1):55-62

S . Bhatia , R . Miller , M . Haddock , J . Donohue , S . Krishnan Adjuvant therapy for ampullary carcinomas: The Mayo Clinic experience . 
International Journal of Radiation OncologyBiologyPhysics , Volume 66 , Issue 2 , Pages 514 - 519

PET scan for GIST

PET is often sued for staging and monitoring of resposne 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.' (2)  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 a would approve GIST for stagin, I would not do so for monitoring of therapy response, as in this case, as being medically necessary, unless a surgical decision is pending, which is not reflected in the record.

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.

Intrahepatic chemotherapy for colon cancer metastases

The potential value of hepatic intra-arterial chemotherapy (HIAC) can be considered from several different perspectives. A fundamental assumption for this discourse requires that, in this evaluation, HIAC is being provided with the intent of providing regional hepatic therapy for metastatic hepatic disease. Despite advances in colon cancer (CRC) screening, surgical techniques, and several novel adjuvant agents, CRC continues to be a significant medical challenge. In the United States, approximately 130,000 cases of colon cancer are diagnosed annually. Of these patients, approximately 60% will ultimately develop metastatic disease, and <30% of the initial patient population will have disease confined to the liver.

Ample evidence exists in support of HIAC as the preferred route of administration of regional hepatic chemotherapy: it achieves higher intrahepatic drug concentrations and excellent tumor response rates when compared with other routes of administration. HIAC is an effective form of regional chemotherapy for hepatic metastases. Nearly all studies demonstrate a tendency toward or a significant decrease in hepatic tumor progression when HIAC is used. It is also clear from the data reviewed that regional control of hepatic disease without or independent of systemic disease control does not confer a survival advantage.

To date, the QOL of patients undergoing HIAC has not been adequately evaluated or compared with other treatment modalities. The studies available do not permit any conclusions about the QOL of patients receiving HIAC. Future studies should include QOL among the secondary outcomes in evaluating HIAC.

To date, 10 RCTs have been published, for a total of 1,277 patients enrolled. For tumor response rates, relative risks (RR) and their 95% CIs were obtained from raw data; for OS, hazard ratios (HRs) and their 95% CIs were extrapolated from the Kaplan-Meier survival curves.

Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

Going to a different setting, 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.

http://www.annalssurgicaloncology.org/cgi/reprint/13/2/142.pdf

Evan S. Ong, MD, Madeleine Poirier, MDCM, MSc, FRCS(C) and N. Joseph Espat, MD, MS, FACS
Hepatic Intra-Arterial Chemotherapy Annals of Surgical Oncology 13:142-149 (2006)

S. Mocellin, P. Pilati, M. Lise, and D. Nitti
Meta-Analysis of Hepatic Arterial Infusion for Unresectable Liver Metastases From Colorectal Cancer: The End of an Era?
J. Clin. Oncol., December 10, 2007; 25(35): 5649 - 5654.

Pancreatic cancer treatment based on BRCA mutations status

The concept of individualized therapy is beint tesed in clincial trial. One such trial  in patients with pancreatic cancer is being run by researchers at Johns Hopkins University. The trial will enroll patients with previously untreated, advanced or recurrent pancreatic cancer and a mutation in the BRCA2 gene. The BRCA2 gene confers greatly increased risk of breast and ovarian cancer in addition to a substantial increase in pancreatic cancer risk. Previous studies showed that pancreatic tumors from patients with a BRCA2 gene mutation were approximately 1,000 times more sensitive to mitomycin-C than were tumors from patients without the BRCA2 gene mutation. If this study confirms these data, then a diagnostic test to determine the BRCA2 status of the pancreatic cancer patients may be indicated to determine the appropriate chemotherapy prior to initiating treatment in pancreatic cancer. The clinical trial now underway is designed to determine whether the extreme sensitivity of the pancreatic cancer to mitomycin-C holds true in humans as it did in earlier studies. A total of 35 patients with BRCA2 mutations will be enrolled for treatment with mitomycin-C during the course of the study. The study will compare the six-month survival rate of treated patients with the current survival rates from standard of care therapy to determine the potential benefit of using mitomycin-C for people with BRCA2 gene mutations. Previous study results led the researchers to expect a substantial improvement in the six-month survival time of pancreatic cancer patients.Mitomycin-C is one member of an important class of DNA damaging agents used to treat cancer. BRCA2 is part of the DNA repair process. When mitomycin-C damages the DNA in a patient's cancer cells, the damage would normally be repaired with the help of BRCA2. If there is no BRCA2 to fix the DNA, because of a BRCA2 gene mutation, the mitomycin-C damage is not repaired, the cancer cells die and the drug is more effective.

At this time, the strategy of diagnosing BRCA in order to provide individualized therapy remains investigational.

NCCN.ORG. Pancreatic Cancer

Julia B Greer, David C Whitcomb et al, Role of BRCA1 and BRCA2 mutations in pancreatic cancer Gut 2007;56:601-605

PET for GIST

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract (GIT). About 5000 to 6000 new cases of GISTs are diagnosed in the United States annually. Response to conventional chemotherapeutic agents and radiation therapy is disappointing. Early experience with the tyrosine kinase inhibitor, STI-571 (Gleevec, imatinib mesylate), has been extremely encouraging and it is now an FDA approved treatment.

The role pf PET is udner investigation. Positron emission tomographic scanning with the radiotracer 18F-FDG can reveal early functional changes in tumor glucose metabolism that appear to correlate closely with metabolic response to imatinib mesylate. 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 response to drug therapy could be shown as early as 24 hours after completion of a therapeutic regimen.Though very promising, the number of reporteds and the number of published papers is too small to definitely assess sensitivity of PET and PET/CT in evaluating GIST response, as this malignancy is rare. A larger, multicenter study is required.

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.

Van den Abbeele AD, for the GIST Collaborative PET Study Group. F18-FDG-PET provides early evidence of biological response to STI571 in patients with malignant gastrointestinal stromal tumors [abstract]. Proc Am Soc Clin Oncol. 2001;20:362a; Abstract 1444.

Gemcitabine and irinotecan for pancreatic cancer

Lay Summary: Gemcitabine and irinotecan appears to be no better than gemcitabine alone

The combination of irinotecan and gemcitabine has been studied in pancreatic cancer. Rocha Lima and colleagues randomized 360 patients to either gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 on days 1 and 8 every 21 days (gem/irino) or the standard gemcitabine regimen (gem). The arms were well balanced as to age, performance status, metastatic disease, and prior radiotherapy. Diarrhea and nausea/vomiting were worse for patients on the gem/irino arm. While the gem/irino combination was associated with a higher response rate, overall survival and time to tumor progression were similar in both groups. The overall survival for the gem/irino and gem arms was 6.3 months and 6.6 months, respectively. Except for diarrhea, toxicity was very similar between both groups.

The combination of gemcitabine and irinotecan was clearly no better than single-agent gemcitabine. The study that compared the regimens should serve as a cautionary note to investigators regarding phase 2 results. While promising results from the phase 2 study of gemcitabine and irinotecan prompted the launch into this phase 3 trial, it is becoming increasingly clear that response rates in phase 2 trials for pancreatic cancer are often unreliable surrogates for overall survival. For example, in the phase 2 study, the median survival was 5.7 months, which is very similar to the 6.3-month median survival seen in the phase 3 study.

Rocha Lima CM, Sherman CA, Brescia FJ, Brunson CY, Green MR.Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer.Oncology (Williston Park). 2001 Mar;15(3 Suppl 5):46-51.

PET for pancreatic cancer

Pancreatic carcinoma is common in the United States, with approximately 30,000 patients each year diagnosed with pancreatic adenocarcinomas. Patients with inflammatory processes in the pancreas (pancreatitis) but no cancer can sometimes have high FDG uptake that is indistinguishable from cancers and, thus, must be differentiated from patients with cancer. FDG PET is being applied increasingly in pancreatic cancer diagnosis.
A recent literature review of all available studies found this:
For diagnosis: An estimated 50% change was noted in management effect, based on 26 patient studies. For diagnosis/staging: An estimated 43% change was noted in management effect, based on 65 patient studies. For staging: An estimated 36% change was noted in management effect, based on 33 patient studies. For recurrence: An estimated 53% change was noted in management effect, based on 19 patient studies. For monitoring response: An estimated 16% change was noted in management effect, based on 19 patient studies.

Considering the very poor prognosis of pancreatic carcinomas, PET´s greatest role may prove to be in helping to characterize masses appearing in the pancreas, as opposed to more general tumor staging. This is an active area of current investigation.

http://www.petscaninfo.com/zportal/portals/phys/clinical/jnmpetlit/index_html/JNM_OncoApps

CA-19-9 for gastric cancer

CA 19-9 is elevated in some cases of gastric cancer and in those cases it is often used to monitor response to chemotherapy. Approximately one third of patients with gastric cancer will have elevated levels of CEA and one third will have elevated levels of CA 19-9; Ca 19-9 is more commonly elevated in pancreatic and biliary cancer. It can be used for detecting early relapse or to monitor therapy. Unfortinately, there is not much credible medical literature defining these used for specifically gastric cancer and many plans, including Anthem do not consider 19-9 to be a medically necessary marker to follow gastric cancer. This approach is defensible based on the literature. Although there is set of Japanese guidelines that recommends Ca 19-9, gastric cancer in Japan is a differently behaving  disease than in the West, as is widely recognized, and Japanese practice in gastric cancer is not followed in the USA.

M.J. Gaspara, I. Arribasa, M.C. Cocaa, M. Díez-AlonsobPrognostic Value of Carcinoembryonic Antigen, CA 19-9 and CA 72-4 in Gastric Carcinoma Tumor Biology Vol. 22, No. 5, 2001

V Heinemann, J Stemmler, M Schermuly, P Stieber, K Niebler, R Wilkowski, T Helmberger, M Garbrecht, A Schalhorn CA 19-9: An Early Indicator of Response to Chemotherapy in Advanced Pancreatic Cancer.  Proc Am Soc Clin Oncol 19: 2000 (abstr 1076)

Pediatric testicular cancer

Malignant germ cell tumors (MGCT) account for 3% to 4% of childhood malignancies (< 15 years of age). Before the advent of multimodal therapy, children with MGCT could expect poor outcomes. Subsequent therapy was based on the larger adult experience with epithelial ovarian cancer because there was a paucity of clinical trials in pediatric patients. Cyclophosphamide-based therapy improved the outcome for patients with localized MGC  but for patients with advanced disease, outcome remained poor. The Einhorn regimen dramatically improved the outcome of adults with testicular MGCT and quickly became the standard of care. Concerns about the potential toxicity of cisplatin and bleomycin limited use of this combination in pediatric patients. Most pediatric studies incorporated these agents in combination with cyclophosphamide-based therapy. An excellent 2-year disease-free survival rate was reported for 13 children treated with cisplatin-based therapy.

Boys and adolescents with stages III and IV testicular tumors are treated with surgical resection followed by four courses of standard or high-dose PEB (platinum, etoposide, bleomycin) therapy. The 6-year survival outcome for stage III and IV males younger than 15 years was 100%, with 6-year EFS of 100% and 94%, respectively. The use of high-dose PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular germ cell tumors using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II–IV tumors have also been reported by European investigators. Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II–IV testicular germ cell tumors in children younger than 15 years.

N. Marina, W. B. London, A. L. Frazier, S. Lauer, F. Rescorla, B. Cushing, M. H. Malogolowkin, R. P. Castleberry, R. B. Womer, and T. Olson
Prognostic Factors in Children With Extragonadal Malignant Germ Cell Tumors: A Pediatric Intergroup Study
J. Clin. Oncol., June 1, 2006; 24(16): 2544 - 2548

Paul C. Rogers, Thomas A. Olson, John W. Cullen, Deborah F. Billmire, Neyssa Marina, Frederick Rescorla, Mary M. Davis, Wendy B. London, Stephen J. Lauer, Roger H. Giller, Barbara Cushing, Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891 Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3563-3569

PDQ - http://www.cancer.gov/cancertopics/pdq/treatment/extracranial-germ-cell/HealthProfessional/page8

XelOx

The XelOx regimen is currently quite popular. 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. The latest version of the NCCN Colon Cancer Guidelines include several major changes to recommended courses of treatment based on recent relevant clinical studies and changing practice patterns. One significant change is the recommendation of capecitabine (Xeloda) and oxaliplatin (Eloxatin) also known as CAPOX as a treatment option in first-line therapy. Whether Avastin is helpful with this regimen is under study in a phase III trial.

Kocha W, Maroun J, Jonker D, Rumble RB, Zuraw L, Gastrointestinal Cancer Disease Site Group. Oral capecitabine (Xeloda) in the first-line treatment of metastatic colorectal cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Feb 11. 27 p. (Evidence-based series; no. 2-15). [30 references] NCCN.ORG, Golon