Cancer Treatment

Xeloda for nasopharyngeal cancer

Nasopharyngeal carcinoma is endemic in Southeast Asia and China with increased incidences in the Mediterranean countries. It is relatively rare in the United States and Continental Europe. It differs markedly from other head and neck cancers based on its distinct histology, its association with EBV, its marked responsiveness to chemotherapy, and its rapid growth with early dissemination. Presentation is commonly a locally advanced stage with nodal involvement or metastases.

A combined modality approach with chemotherapy and radiation has become standard treatment for nasopharyngeal carcinoma. The most notable prospective trial to date examined induction with 5-FU and cisplatin followed by radiation. Since the introduction of effective chemotherapy as part of the salvage treatment after relapse in these patients with nasopharyngeal cancer, the 5-year survival rate in patients with stage IV disease who received radiation therapy as their initial treatment has risen to the 40% range.

Capecitabine has been studies in a number of phase II studies, especially Chinese studies, yielding response rates of 20-30+%. One study claimed 48% response. Overall, the studies suggest that it is a moderately effective treatment and supported by several phase II trials. A phase I trial has been completed with radiation: Phase I Trial of Induction Paraplatin® and Xeloda® Followed by Concurrent Paraplatin and Xeloda With Intensity Modulated Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Al-Sarraf M, Reddy MS. Nasopharyngeal carcinoma. Curr Treat Options Oncol. 2002;3:21-32.

Mould RF,Tai TH. Nasopharyngeal carcinoma: treatments and outcomes in the 20th century. Br J Radiol. 2002;75:307-339.

Ciuleanu E, Irimie A, Ciuleanu TE, Popita V, Todor N, Ghilezan N.
Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study.
J BUON. 2008 Jan-Mar;13(1):37-42.

Chua D, Wei WI, Sham JS, Au GK.
Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer.Jpn J Clin Oncol. 2008 Apr;38(4):244-9.

Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy.Oral Oncol. 2003 Jun;39(4):361-6.

Sprycel for breast cancer

Dasatinib, also known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. There are several trials, two completed and several ongoing of this drug in breast cancer (http://clinicaltrials.gov/ct2/results?term=dasatinib+breast).
There are studies that show that it is effective alone or with doxorubicin and cusplatin in cell cultures. A phase I and pahse II trial reproted as poster adn abstract respectively suggest that it has modes efficacy in combination with capecitabine. More studies clearly need to be performed.

http://www.posters2view.com/sabcs08/viewp.php?nu=3118

G. Somlo, F. Atzori, L. Strauss, A. Rybicki, X. Wu, W. Gradishar, J. Specht;Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004.J Clin Oncol 27:15s, 2009 (suppl; abstr 1012)

Tryfonopoulos, D., O'Donovan, N., Corkery, B., Clynes, M., Crown, J.
Activity of dasatinib with chemotherapy in triple-negative breast cancer cells
J Clin Oncol (Meeting Abstracts) 2009 27: e14605

HERmark when IHC is definitively negative

HERmark Breast Cancer Assay precisely quantifies HER2 total protein and HER2 homodimer levels in Formalin Fixed Parrafin Embedded Tissue. The preliminary results of one study presented at the most recent ASCO Annual Meeting (Leitzel et al, Abstract 1002), indicate that this assay was a better predictor than FISH testing of response to trastuzumab.
The preliminary results also indicated discordance between assessments of HER2 status as measured by the HERmark assay and FISH. Specifically, 14% of FISH-negative patients were determined to be HER2 high expressors by HERmark, and 13% of FISH-positive patients were determined to be HER2 low expressors. Determination of HER-2/neu status has thus taken on great importance in the routine work-up of breast cancer in the pathology laboratory:over-expression of the protein product of HER-2/neu gene is usually a direct consequence of gene amplification, in which multiple copies of the gene appear throughout the genome. The two most widely used technologies are immunohistochemistry (IHC) and FISH, because these two techniques are ideal for use on paraffin embedded tissue, including archival material.FISH is considered the gold standard for HER2 assessment and correlates best with outcome and response to traztuzamab treatment.While FISH detects gene amplification, IN+HC detects gene product overexpression.In relation to IHC methods of HER assessments, FISH is usually considered superior. It would stand to reason that HERmark is superior to IHC.

However, no direct comparisons have been carried out. ASCO/CAP guidelines recommend that HER2 status be determined for all invasive breast cancer patients. These guidelines caution that current HER2 testing methods (central IHC and FISH) may be inaccurate in up to 20% of cases. HERmark Breast Cancer Assay precisely quantifies HER2 total protein and HER2 homodimer levels in FFPE. HERmark reclassified up to 25% of samples from a cohort of the FinHer Adjuvant Breast Cancer Study. It is not known whether there is a benefit to test by two modalities or not and HERmark is oly one a panoply of next generation of HER tests that are available or coming the the market.

1.Bast RC Jr, Ravdin P, Hayes DF, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865-1878.
2.Carlson RW, Moench SJ, Hammond ME, et al. HER2 testing in breast cancer: NCCN Task Force report and recommendations. J Natl Compr Canc Netw. 2006;4(suppl 3):S1-S24.
3.Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118-145.
4.Lipton A, Ali SM, Leitzel K, et al. HER2 protein expression predicts response to trastuzumab in FISH positive patients. Oral Presentation at 31st Annual San Antonio Breast Cancer Symposium: December 10-4, 2008, San Antonio, TX

Molecular scintigraphy (BSGI) for primary breast lesions

Breast-specific -imaging (BSGI), also known as molecular breast imaging, is breast scintigraphy using a small-field-of-view -camera and 99mTc-sestamibi. Teh technology, especially the types of camers, continues to evolve. Although it is specific, 86%–89%,  it has a relatively low positive predictive value, especially in dense breast tissue.  In addition, correlation of the scintimammography images with ta mammogram is challenging.
BSGI can be  used in patients who have radiodense breast tissue, breast implants, or unexplained architectural distortion or in whom MRI is indicated but not possible. Other uses include evaluation of indeterminate areas identified by mammography or ultrasound, evaluation of multiple lesions or clusters of microcalcifications to aid in biopsy target selection, evaluation of the axillary region for node status in breast cancer patients, and postsurgical or posttherapeutic evaluation of mammographic tissue changes. In addition, BSGI can be used to investigate a palpable mass not demonstrated on mammogram or ultrasound, detect multicentric and multifocal disease or bilateral disease, determine the extent of the primary lesion, and screen a high-risk  However, the indications have not been fully defined and guideliens have not been issued.

Brem RF, Floerke A, Rapelyea J, Teal C, Kelly T, Mathur V. Breast specific gamma imaging as an adjunct imaging modality for the diagnosis of breast cancer. Radiology. 2008;247:651–657.

Zhou M, Johnson N, Gruner S, et al. Clinical utility of breast specific gamma imaging for evaluating disease extent in the newly diagnosed breast cancer patient. Am J Surg. 2009;197:159–163.[

Avastin for ependymoma

Ependymoma is a rare type of glioma, representing 5% of all CNS malignancies, that can recurr in the spinal cord. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. There are several ongoing trials in different combination but not with Temodar: http://clinicaltrials.gov/ct2/results?term=avastin++ependymoma+.

 At recurrence, ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed but the optimal combination is not defined and there are no phase III trials. 

R. M. Green, T. Cloughesy, R. Stupp, L. M. DeAngelis, E. A. Woyshner, D. E. Ney, A. B. Lassman; Kaiser Foundation Hospital, Los Angeles, CA Bevacizumab for recurrent ependymoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 2060)

Green, R. M., Cloughesy, T. F., Stupp, R., DeAngelis, L. M., Woyshner, E. A., Ney, D. E., Lassman, A. B.
Bevacizumab for recurrent ependymoma
Neurology 2009 73: 1677-1680

Suspected brain metastases: The role of PET

Biopsying the primary lesions is technically difficult since it is located in the cerebellum. Studies of PET have focused on the population with a biopsy proven source of metastases. For example, in one study of biopsy proven cancer of unknown origin, a survey on clinical usefulness of PET (response rate 83%) suggested that PET positively contributed to diagnostic understanding in 29 of 52 evaluable cases. It concluded that late in the diagnostic trajectory, approximately four patients need to be scanned by PET in order to find one primary tumour. However, in addition to direct demonstration of unknown primaries, there appears to be a positive effect on the diagnostic work-up of these patients of a similar magnitude.

A 1999 study found that PET identified focal hypermetabolic abnormalities in 19 of 22 intracranial metastases, 2 hypometabolic lesions, and 1 renal cell tumor embolism that hemorrhaged (hypometabolic lesion). It also identified 82% of extracranial primary tumor sites, of which 55% were found only on PET and not on conventional diagnostic tests. Patients did not have a biopsy proven diagnosis in this study. Another study concluded: " Screening the patients with suspected metastatic brain tumors using whole-body (18)F-FDG PET could be helpful in differentiating metastatic brain tumor from primary brain tumor and in detecting the primary lesion."

 

Joshi, U, van der Hoeven, J J M, Comans, E F I, Herder, G J, Teule, G J J, Hoekstra, O S
In search of an unknown primary tumour presenting with extracervical metastases: the diagnostic performance of FDG-PET
Br J Radiol 2004 77: 1000-1006

D. A. Podoloff
PET/CT and Occult Primary Tumors
J Natl Compr Canc Netw, March 1, 2009; 7(3): 239 - 244.

Peter Nicholson et al, FDG-PET in the Staging Work-Up of Patients with Suspected Intracranial Metastatic Tumors, Ann Surg. 1999 August; 230(2): 202.

Jeong HJ, Chung JK, Kim YK, Kim CY, Kim DG, Jeong JM, Lee DS, Jung HW, Lee MC.
Usefulness of whole-body (18)F-FDG PET in patients with suspected metastatic brain tumors.
J Nucl Med. 2002 Nov;43(11):1432-7.

Maintenance for ovarian cancer

Maintenance is usually defined as treatment to maintain a complete response or best achievable partial response but not therapy that aims to improve response. Unfortunately most patient who achieve response in metastatic disease and many in stage III, ultimately relapse. Maintenance could potentially benefit these patients. There have been several studies with conflicting results. One by Markman et al showed prolongation of disese free survival. A 2003 review stated: "Prospective randomized trials of maintenance strategies should also incorporate formal quality-of-life assessments. Until the completion of additional trials, the results of the study by Markman et al should not routinely be used to recommend maintenance paclitaxel in patients with advanced ovarian cancer who have achieved a complete remission with standard". In 2nd line, Doxil has not shown benefit for maintenance. 2011 NCCN OV-4 recommends paclitaxel maintenance as a 2B option and the discussion states that the experts on the panel disagree about this.

Kaye S, Vasey P. Docetaxel in ovarian cancer: phase III perspectives and future development. Seminars in Oncology. 2002;29(3 Suppl 12):22-7.

Ozols, Robert F. Maintenance Therapy in Advanced Ovarian Cancer: Progression-Free Survival and Clinical Benefit J Clin Oncol 2003 21: 2451-2453
 
Markman M, Liu PY, Wilczynski S, et al. Southwest Oncology Group; Gynecologic Oncology Group. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003;21(13):2460-2465.

E Andreopoulou et al, Pegylated liposomal doxorubicin HCL (PLD; Caelyx/Doxil®): Experience with long-term maintenance in responding patients with recurrent epithelial ovarian cancer Ann Oncol (2007) 18 (4): 716-721.

Xeloda or 5FU, leukovorin and gemcitabine for colorectal cancer

Fluoropyrimidines with oxaliplatin or irinotecan plus bevacizumab is the standard chemotherapy combination in patients with advanced colorectal cancer (CRC). Gemcitabine acts synergistically with fluoropyrimidines to enhance the binding of thymidylate synthase and increase inhibition of DNA synthesis.
The patient appealed based on studies of Xeloda/Gemcitabine and assumes the identity of 5FU/leukovorin to Xeloda, which is far from proven in rectal cancer. Even if assuming such equivalence, it remains an experimental combination; A 2004 study concluded: "This combination regimen has an excellent tolerance in this heavily pretreated patients; the MTP, survival (OS) and the founding of some degree of activity are encouraging. Further studies of this treatment regimen are warranted."
The regimen has more of a track record in pancreatic cancer and renal cell cancer.
 A recent review looked at forty-two advanced CRC patients who were evaluated in two Phase I studies and the maximum tolerated dose of gemcitabine was 900 - 1,000 mg/m(2) weekly with either bolus 5-fluorouracil (5-FU) or capecitabine. A total of 216 advanced CRC patients were evaluated in six Phase II studies. It found that "Fluoropyrimidine plus gemcitabine is clinically active in patients with refractory CRC demonstrating prolonged median time to progression and acceptable toxicity only when bolus 5-FU was not used."
Clinicaltrials.gov lists one study that has been completed but for which no publication has yet been submitted.

Y. Fernández, J. M. Vieitez, J. Fra, I. Palacio, B. Mareque, E. Uña, J. M. Buesa, A. J. Lacave; Hospital Central de Asturias, Oviedo, Spain  Capecitabine plus gemcitabine in heavily pre-treated colorectal cancer. Results of an exploratory study.Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3679

Merl M, Hoimes C, Pham T, Saif MW.
Is there a palliative benefit of gemcitabine plus fluoropyrimidines in patients with refractory colorectal cancer? A review of the literature previously presented: poster at the 2008 Gastrointestinal Cancer Symposium (Abstract No. 512).Expert Opin Investig Drugs. 2009 Sep;18(9):1257-64.

Xeloda and Avastin for maintenance in colon cancer

Avastin was approved for second line therapy in previously Avastin naive patients and this was followed by data anlyses that suggested that Avastin is beneficial for maintenance. A suggestion that Avastin may be modifying disease progression even after it failed to control recurrence comes from a retropective review. BRiTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety) observed progress of three groups of patients when their cancer got worse after their first chemotherapy treatments.  All patients had Avastin as part of the first chemo, some continued it beyond that first cancer progression.

BRiTE patients were treated by their own oncologists in almost 250 different places in the United States. Overall median survival time for the three groups was:

No further treatment after progression:  12.6 months
Chemotherapy, no Avastin:  19.9 months
Chemotherapy with continued Avastin: 31.8 months
Median survival time after first progression

No further treatment: 3.6 months
Chemotherapy only: 9.5 months
Chemotherapy plus Avastin: 19.2 months

It stands to reason that patients who responded and are stable or had a complete response would benefit from continued Avastin. However, this is not yet confirmed. There is no prospective trial evidence and this strategy should be considered experimental until a prospective study confirms it.
There is a great deal of interest in maintenance strategies but which is best and even if any of them is beneficial over observation and retreatment is not known. One trial is: A Study of Avastin (Bevacizumab) and Xeloda (Capecitabine) as Maintenance Treatment in Patients With Metastatic Colorectal Cancer, NCT00623805. This 2 arm study will assess the efficacy and safety of maintenance treatment with Avastin + Xeloda, after initial treatment with Xeloda + oxaliplatin + Avastin, in patients with metastatic colorectal cancer. Patients will be randomized into one of 2 groups to receive 1)Xeloda + oxaliplatin + Avastin until disease progression or 2)Xeloda + oxaliplatin + Avastin for 6 x 3 week cycles, followed by Xeloda + Avastin until disease progression. This is a phase III trial. There is also: Optimal Maintenance Therapy With Bevacizumab After Induction in Metastatic Colorectal Cancer (CRC),NCT00973609, also a phase III study. This is a multicenter study. Patients are stratified according to best response during first-line chemotherapy/bevacizumab treatment (complete response and partial response vs stable disease), duration of first-line treatment (16-20 weeks vs 21-24 weeks), type of chemotherapy used during first-line treatment (irinotecan and fluoropyrimidine vs oxaliplatin and fluoropyrimidine vs fluoropyrimidine monotherapy), disease burden (one organ with metastasis vs more than one organ with metastasis), and by participating center.

•Arm I (bevacizumab maintenance therapy): Patients receive bevacizumab IV over 30 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
•Arm II (no maintenance therapy): Patients receive no further treatment; they are monitored for disease progression. There are also other smilar studies. NCCN has nto yet incorporated maintenace into its guidelines.

K.M. Galal, M. Abdelsalam, E.E. Fawzy, S. Mansour, K. Zaghloul and E.M. Mohamed  Role of Bevacizumab as Post-Progression Maintenance Therapy in Metastatic Colon Cancer Journal of Medical Sciences  Year: 2008 | Volume: 8 | Issue: 5 | Page No.: 452-460

Grothey, Axel, Sugrue, Mary M., Purdie, David M., Dong, Wei, Sargent, Daniel, Hedrick, Eric, Kozloff, Mark
Bevacizumab Beyond First Progression Is Associated With Prolonged Overall Survival in Metastatic Colorectal Cancer: Results From a Large Observational Cohort Study (BRiTE)
J Clin Oncol 2008 26: 5326-5334

S. Kopetz and J. L. Abbruzzese
Hidden Biases in an Observational Study of Bevacizumab Beyond Progression
J. Clin. Oncol., April 1, 2009; 27(10): 1732 - 1733.

L. M. Ellis and D. G. Haller
Bevacizumab Beyond Progression: Does This Make Sense?
J. Clin. Oncol., November 20, 2008; 26(33): 5313 - 5315.

Cohn AL, Bekaii-Saab T, Bendell JC, et al. Clinical outcomes in bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): results from ARIES observational cohort study (OCS) and confirmation of BRiTE data on BV beyond progression (BBP). J Clin Oncol 28(suppl 15):284s. ASCO Abstract #3596.

Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): the MACRO trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). J Clin Oncol 28(suppl 15):261s. ASCO Abstract #3501.

 

 

Celebrex for melanoma

Celecoxib, sold under the brand name of Celebrex by Pfizer Inc., is a non-steroidal anti-inflammatory drug which has anti-angiogenic properties and has been explored in a nubmer of cancers both therapeutically and for prevention. Expression of COX-2 in malignant melanoma has been investigated by immunohistochemistry in 28 cases of primary skin melanoma and four benign nevi. COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. These results indicate that COX-2 is expressed in malignant melanoma and may be involved in regulation of melanoma invasion. Another group failed to demonstrate COX-2 expression in melanoma tissue samples, but showed that COX-2 inhibitors were able to induce apoptosis in melanoma cells independently of enzyme expression.
One recent study in melanoma patients with surgically incurable recurrent melanoma, 87 percent of whom had stage M1c diseaseshowed regressions in 7 of 27 patients (2 complete regressions, 2 partial regressions, and 3 mixed stable/partial response). For all patients, median overall survival time from first incurable metastasis was 31.9 months, and median times to progressive disease and death from start of celecoxib were 4.3 months and 10.4 months, respectively. I was not able to find otehr trials of Celbrex alone in melnoma. There is also a published combination study with temazolamide.There is an ongoing combination trial: Phase I/II Study of Celebrex and EPO906 in Patients With Metastatic Colorectal Cancer, NCT00159484.  Celebrex should be considered investigational for treatment of melanoma.

Kenneth S. Wilson Clinical Activity of Celecoxib in Metastatic Malignant Melanoma
Cancer Investigation 2006, Vol. 24, No. 8, Pages 740-74

Melanoma: prevention, detection, and treatment By Catherine M. Poole, DuPont Guerry, Yale University Pres p. 137, 2006

H Gogas et al, Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group
Oxford Journals&MedicineAnnals of OncologyVolume 17, Issue 12, 2006