Cancer Treatment

Oxaliplatin and Rituxan for Hodgkin's

Rituxan is a promising drug for Hodgkin's but more studies need to be done. Oxaliplatin is currrently in a clinical trial: Oxaliplatin in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma., NCT00006473, completed but not published yet. It is a Phase II trial to study the effectiveness of oxaliplatin in treating patients who have relapsed or refractory non-Hodgkin's lymphoma.

According to results recently published in the journal Blood, Rituxan® (rituximab) appears to be a promising agent in the treatment of some patients with recurrent Hodgkin's. Rituxan® is a monoclonal antibody approved for treatment of non-Hodgkin’s lymphoma (NHL) and binds to an antigen called CD 20. A small subset of patients with Hodgkin’s lymphoma (3% to 8%) has a type of cancer called CD 20 lymphocyte predominant Hodgkin’s lymphoma, characterized by a large proportion of their cancer cells expressing CD 20. Patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma tend to have a higher rate of recurrence following standard therapy than other patients with Hodgkin’s lymphoma. 

Researchers from Germany recently conducted a clinical trial to evaluate the effectiveness of Rituxan® in the treatment of recurrent Hodgkin’s lymphoma. The trial involved 14 patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma, or Hodgkin’s lymphoma with over 30% of their cancer cells expressing CD 20. Patients were on average 9 years from diagnosis and had stopped responding to at least one prior therapy. Overall, 12 patients had an anti-cancer response to Rituxan®, with 8 patients achieving a complete disappearance of detectable cancer and 4 patients achieving a partial anti-cancer response. Two patients had progressive disease. One year following therapy, 9 of the 12 responding patients demonstrated no signs of cancer progression. Furthermore, at over 20 months following therapy, the average duration of responses has not yet been reached. Side effects were generally mild and moderate, allowing for the majority of patients to receive treatment on an outpatient basis.

The researchers concluded that Rituxan® is a viable treatment option for patients with relapsed Hodgkin’s lymphoma that expresses the CD 20 antigen clinical trials.

Combination of the two was recenlty tried in 8 elderly relapsed/ reefractory patients. One complete response, 3 partial response and 3 minimal response were obtained at 11 months of median time follow-up.

The combination of these two drugs with gemcitabine has recently been reported as well in a single phase II study. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo.

In summary, there are two Phase II trials that demonstrate some effectiveness of Rituxan in a specific subset of Hodgkin’s Lymphoma. First, it needs to be determined if the patient has lymphocyte predominant disease. Most plans will consider this therapy to be investigational but where coverage is availble it is certainly an interesting and promising option.

Rehwald U, Schultz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101:420-424.

Rehwald U, Schulz H, Reiser M, et al. German Hodgkin Lymphoma Study Group (GHSG): treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101: 420-424.

D. Re, R. K. Thomas, K. Behringer, and V. Diehl
From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential
Blood, June 15, 2005; 105(12): 4553 - 4560.

Addeo R, Caraglia M, Costanzo R, Faiola V, Montella L, Abbruzzese A, Del Prete S. Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non-Hodgkin's lymphoma of elderly patients. Oncol Rep. 2004 Jul;12(1):135-40

T El Gnaoui , J Dupuis , K Belhadj , J-P Jais , A Rahmouni , C Copie-Bergman , I Gaillard , M Diviné , I Tabah-Fisch , F Reyes , and C Haioun Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy
Annals of Oncology Advance Access published on August 1, 2007, DOI 10.1093/annonc/mdm133.
Ann Oncol 18: 1363-1368.

 

Clofarabine for adults

Clofarabine is approved by the Food and Drug Administration (FDA) to treat relapsed or refractory acute lymphoblastic leukemia (ALL) in pediatric patients who have already had at least two other types of treatment. Clofarabine is also being studied in the treatment of other types of cancer.

In a European multi-center study, clofarabine was administered first line, as a monotherapy, to 30 patients over 60 years of age with AML and 13 (43%) patients achieved a complete response (CR); 4 (13%) patients achieved a complete response without full platelet recovery (CRp); and 3 (10%) achieved a partial remission (PR), thus giving an overall response rate of 66%. This compared favorably with the current best standard of care, low-dose ara-C, which achieved a CR rate of 17% in the AML 14 Trial conducted by the UK National Cancer Research Institute. The duration of remission observed with clofarabine was also durable with the interim follow-up at a median of at least 6 months. An application has been submitted to the FDA for approval for adult AML. A phase II study concluded: "These interim data indicate that single agent CLO is active and well-tolerated in treatment-naïve, older AML patients with 1 adverse prognostic factor, especially unfavorable risk karyotype and/or AHD."

There is another study going on: Clofarabine Combinations in Relapsed/Refractory AML, MDS and Myeloid Blast Phase CML, NCT00067028. There has been no phase III trial confriming that Clofarabine is superior to 7+3 in any setting.

E, Robak T.Novel purine nucleoside analogues for hematological malignancies.Korycka A, Lech-Marańda Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):123-36

Larson RA.Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine.Semin Oncol. 2007 Dec;34(6 Suppl 5):S13-20.

Hypercoagulability and homocystein

Hypercoagulable states can be defined as a group of inherited or acquired conditions associated with a predisposition to venous thrombosis, arterial thrombosis, or both. Venous thromboembolic disease is the most common clinical manifestation resulting from hypercoagulable states. Among them is hyperhomocysteneimia. Hyperhomocysteinemia can be precipitated by both genetic defects and acquired medical conditions, including vitamin deficiency states.

Inherited severe hyperhomocysteinemia (plasma level higher than 100 mmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR or CBS deficiencies and, more rarely, from inherited errors of cobalamin (vitamin β12) metabolism. Inherited mild to moderate hyperhomocysteinemia (plasma level between 15 and 100 mmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the C677T gene polymorphism, which is the most common mutation in the gene that codes for the MTHFR enzyme. Individuals who are heterozygous for the tlMTHFR variant have normal plasma homocysteine levels, whereas homozygous carriers may have mild to moderate fasting hyperhomocysteinemia in the setting of concomitant folate deficiency.  However, homozygosity for the tlMTHFR in the absence of hyperhomocysteinemia does not appear to be associated with an increased risk of VTEs, and most patients with hyperhomocysteinemia do not have the tlMTHFR polymorphism. Excess homocysteine in the plasma is the risk factor and is the target of therapeutic intervention, not the C677T mutation. The pathophysiology of thrombosis in hyperhomocysteinemia is also unclear. Acquired homocyteneiamia may present in the absence of MTHFR mutation.

Colleen M. Johnson, MD Hypercoagulable States: A Review Vascular and Endovascular Surgery, Vol. 39, No. 2, 123-133 (2005)

Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

De Stefano V, Casorelli I, Rossi E, et al: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305-311

ALIMTA for squamous lung cancer

On September 26, 2008, the U. S. Food and Drug Administration (FDA) approved pemetrexed injection (Alimta Injection, Eli Lilly and Company) for use in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC).  Pemetrexed is not indicated for treatment of patients with squamous cell lung carcinoma.

A multicenter, randomized, open-label study in 1725 patients with stage IIIb/IV NSCLC who had not received prior chemotherapy was conducted to compare overall survival following treatment with pemetrexed plus cisplatin (AC) to gemcitabine plus cisplatin (GC).  The median survival was 10.3 months in the AC arm and 10.3 months in the GC arm [adjusted hazard ratio 0.94 (95% CI:  0.84, 1.05)].  The median progression-free survival was 4.8 and 5.1 months for the AC and GC arms, respectively [adjusted hazard ratio 1.04 (95% CI:  0.94, 1.15)].  The overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively.

A pre-specified analysis of the impact of NSCLC histology on overall survival was conducted in this trial. Clinically relevant differences in survival according to histology were observed.  In the non-squamous cell NSCLC subgroup the median survival was 11.0 and 10.1 months in the AC and GC groups, respectively [unadjusted hazard ratio 0.84 (95% CI: 0.74, 0.96)].  However, in the squamous cell histology subgroup the median survival was 9.4 versus 10.8 months in the AC and GC groups, respectively [unadjusted hazard ratio 1.22 (95% CI: 0.99, 1.50)].  This unfavorable effect on overall survival associated with squamous cell histology observed with pemetrexed was also noted in a retrospective analysis of the single-agent trial of pemetrexed versus docetaxel in patients with stage III/ IV NSCLC after prior chemotherapy.  Single-agent pemetrexed was approved in 2004 for this more heavily treated lung cancer population.  Current product labeling has been revised to recommend that Alimta is also not indicated in patients with squamous cell lung cancer after prior chemotherapy.

FDA:  http://www.fda.gov/CDER/Offices/OODP/whatsnew/Alimta.htm

Avastin and Tarceva for lung cancer

Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer, and >60% of patients with NSCLC present with locally advanced or metastatic (stage III/IV) disease at initial diagnosis.

Historically, first-line treatment for patients with advanced NSCLC has been platinum-based doublet chemotherapy, in combination with a third-generation cytotoxic compound such as gemcitabine or docetaxel. However, response to first-line chemotherapy is generally short lived, with progression occurring, on average, 4–6 months after treatment is discontinued and a median survival duration of only 8–11 months.

Recently, the combination of erlotinib and bevacizumab has displayed very encouraging activity in a randomized phase II trial in patients with previously treated NSCLC. In one recently reported trial, called Atlas, patients were initially treated with Avastin plus chemotherapy followed by the addition of Tarceva to Avastin in the maintenance phase. Genentech said the trial was stopped early (Feb. 2009) after an interim analysis found that combining Avastin, known generically as bevacizumab, and Tarceva, or erlotinib, significantly extended the time patients with non-small cell lung cancer lived without their disease advancing.
Combination of bevacizumab and Tarceva is being investigated, for example in SO635 trial and in others as well. One such trial is NSCLC (Non-Small Cell Lung Cancer), NCT00095225, A Study to Evaluate Bevacizumab and Chemotherapy or Tarceva in Treating Recurrent or Refractory NSCLC (Non-Small Cell Lung Cancer).

Rabiya S. Tuma Success of Bevacizumab Trials Raises Questions for Future Studies
J. Natl. Cancer Inst. 97: 950-951.
 
Herbst RS, Fehrenbacher L, Belani CP et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 2007;25:4743–4750

Herbst, Roy S. , Sandler, Alan
Bevacizumab and Erlotinib: A Promising New Approach to the Treatment of Advanced NSCLC
Oncologist 2008 13: 1166-1176;

PET for thymus cancer

Thymoma is a n uncommon cancer of the thymus. Limited information is available about sensitivity and specificity of PET for thymojma. Unfortunately, baseline thymic uptake is common. One study examined thymic uptake at 18F-FDG PET in 94 patients ranging from 18 to 29 years of age and found that 32 of these patients exhibited normal physiologic thymic uptake. The criteria for "normal" in these patients included a normal thymus identified at CT, absence of clinical symptoms of thymus-related disease, and absence of mediastinal tumor at follow-up ranging from 6 to 69 months.
Sasaki et al found a mean SUV of 7.2 ± 2.9 for patients with thymic carcinoma (n = 9). This value was significantly greater than the values found for invasive thymoma (3.8 ± 1.3) and noninvasive thymoma (3.0 ± 1.0). By using an SUV of 5.0 as a cutoff, the authors achieved reasonable sensitivity (84.6%), specificity (92.3%), and accuracy (88.5%) in differentiating thymic carcinoma from thymoma. They found no statistically significant difference in SUV between invasive and noninvasive thymomas, a finding that is consistent with the histologic similarity of the two tumors. This finding is also consistent with earlier work by Liu et al, which failed to demonstrate a significant difference in 18F-FDG uptake between different stages of thymoma. Brink et al also presented one case of thymic carcinoma with an SUV of 9.6. On the basis of these limited data, it appears that 18F-FDG PET will prove to be effective in differentiating thymic carcinoma from other entities within the thymus but will likely prove equivocal in differentiating invasive and noninvasive thymoma from each other and from thymic hyperplasia. More study is clearly required.

Brett Ferdinand, Pramod Gupta, and Elissa L. Kramer Spectrum of Thymic Uptake at 18F-FDG PET RadioGraphics 2004 24: 1611-1616.

M. M. Abouzied, E. S. Crawford, and H. A. Nabi
18F-FDG Imaging: Pitfalls and Artifacts
J. Nucl. Med. Technol., September 1, 2005; 33(3): 145 - 155.

Miraluma scintimammography

Scintimammography is a diagnostic modality using radiopharmaceuticals to provide tumor-specific imaging of the breast. Scintimammography has been proposed primarily as an adjunct to mammograms as a technique to improve patient selection for biopsy. If sufficiently predictive of benign lesion, scintimammography might be used to recommend against performing a biopsy, thus reducing the number of negative biopsies. If scintimammography accurately assesses axillary lymph node status, patients might either undergo needed axillary dissection or avoid it when unnecessary.
Various different radiopharmaceuticals may be used, including but not limited to technetium-99m sestamibi (Miraluma®), thallium-201, indium-111 satumomab pendetide (Oncoscint CR/OV®), and technetium-99m arcitumomab (CEA-Scan®). At the present time, only technetium-99m sestamibi has specific FDA approval for use in breast imaging. The labeling states that technetium-99m arcitumomab (CEA-Scan®). At the present time, only technetium- 99m sestamibi is a second-line diagnostic test after mammography to assist in the evaluation of breast lesions in patients with an abnormal mammogram of breast mass. It is not indicated for breast cancer screening or to confirm the presence or absence of malignancy, and it is not an alternative to biopsy prompted by an abnormal mammogram or breast mass.

Medicare covers this test under soe conditions: "Miraluma as an aid in mammography will be covered with the following indication: Medical record indicates radiopharmaceutical used as a second line diagnostic drug after mammography to assist in the evaluation of a new breast lesion with abnormal mammogram or new palpable breast mass. Miraluma will not be covered if utilized for breast cancer screening, or for confirmation of presence or absence of malignancy of the breast. Miraluma is not an alternative to biopsy or mammogram. Miraluma is not covered for diagnoses of fibrocystic disease or pre-existing mass. Many private payers deny payment in allc ases basing themselves on a BCBS TEC assessment of 1997.  A 1997 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (2) reviewed the available published evidence for this indication and concluded that as a second-line diagnostic test after mammography, the sensitivity and corresponding negative predictive value of scintimammography were not high enough to influence treatment decisions. Specifically, even at the low end of the intermediate range of prevalence for malignancy, if a negative scintimammogram were to be used to recommend against doing biopsy, the risk of undetected malignancy would be 4.5%. This was considered too high given the relatively low morbidity of breast biopsy, the gold standard.  An updated search of the published literature identified an additional small case series focusing on patients with microcalcifications; scintimammography was used to deselect patients for biopsy. The negative predictive value in this study was only 63%.

http://www.rgbagov.com/publications/lcd/lcd-files/044-97k.html

Agency for Healthcare Research & Quality. (2006, February). Noninvasive tests may miss breast cancer, AHRQ study finds. Retrieved from http://hstat.nlm.nih.gov/ftrs/dbaccess/htr95-9.

Brem, R. F., Rapelyea, J. A., Zisman, G., Mohtashemi, K., Raub, J., Teal, C. B., et al. (2005). Occult breast cancer: Scintimammography with high-resolution breast-specific gamma camera in women at high risk for breast cancer. Radiology, 237 (1), 274-280.

Health Technology Assessment Information Service. TARGET database. (2000, August). Scintimammography. Retrieved March 29, 2006 from ECRI HTAIS.

Liberman, M., Sampalis, F., Mulder, D. S., & Sampalis, J. S. (2003). Breast cancer diagnosis by scintimammography: A meta-analysis and review of the literature. Breast Cancer Research and Treatment, 80 (1), 115-126.

Polan, R. I., Klein, B. D., & Richman, R. H. (2001). Scintimammography in patients with minimal mammographic or clinical findings. Radiographics, 21 (3), 641-653.

TEC Assessment:  Scintimammography, 1997; BlueCross and BlueShield Association Technology Evaluation Center, Vol. 12, No. 19

Gemcitabine and carboplatin for unknown primary

Management of cancers of unknown origin is complex. When the primary site is not identified and when it does not fall neatly into certain specific clinical patterns, empiric broad-spectrum chemotherapy is recommended by NCCN and is generally acceptable. Among the agents that NCCN recommends is gemcitabine and cisplatin. The NCCN also recommends Paclitaxel or docetaxel with carboplatin. There are many trials with carboplatin instead of cisplatin and at various doses. The use of carboplatin should not be considered investigational.

 Among the agents that NCCN recommends is gemcitabine and cisplatin. The doses that it recommends are 1250mg/m2 D1 and 8 and 100mg/m2 every 3 weeks. Gemcitabine, an active drug in several solid tumors, has also found to be useful as secondary therapy for some patients with carcinoma of unknown primary site. Carboplatin is recommended by NCCN in combination with other drugs as well for unknown primary but with gemcitabine it recommends cisplatin. The selection of cisplatin and not carboplatin is eclectic, in my opinion, as phase II trials support carboplatin also.

PDQ says: "The majority of patients will not have a definable primary source. For such patients, a variety of combination chemotherapy approaches have been tried with little success. No treatment can be considered standard at present. Therefore, such patients should be considered for available clinical trials." The NCCN clearly does not agree that there is no standard therapy and carboplatin should be considered standard with gemcitabine  as well as cisplatin. The combination of gemcitabine and carboplatin has the advantage of being able to be administered rapidly in an outpatient setting with myelosuppression (usually dose dependent) being the only frequent major toxicity. Significant nausea, vomiting and alopecia are rare. The spectrum of activity of the combination is such that it would appear to be an ideal combination to use in this setting, provided that colorectal cancer, where carboplatin is inactive, can be reasonably excluded. In most of these settings carboplatin has been shown to be equivalent to cisplatin. 
nccn.org, occult primary

nccn.org, occult primary

K B Pittman et al, Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study British Journal of Cancer (2006) 95, 1309–1313.

Gemcitabine plus carboplatin is "an active and very well-tolerated" therapy against carcinoma of unknown primary site
Inpharma, Volume 1, Number 1570, 2007-01-13 , pp. 18-18(1)

Pegasys for T-cell lymphomas and Mycosis Fungoides

Cutaneous T-cell lymphoma (CTCL) is classified as an indolent hematologic malignancy with distinct clinicopathologic features. Mycosis Fungoides is a subset of CTCL. Although prognosis varies depending on the stage, patients who have cutaneous tumors, lymph node or visceral involvement, or peripheral blood involvement (Sézary syndrome) generally have a poor outcome.
For advanced disease, systemic treatment options include low-dose methotrexate, photopheresis, biologic response modifiers such as bexarotene capsules, vorinostat (Zolinza), interferons, denileukin diftitox (Ontak), and single-agent chemotherapy. Combination therapies can be used when single agents fail or when patients have advanced or progressive disease.

Interferon is a valuable agent in the armamentarium; alfa interferon (IFN)as a single agent has shown partial remission rates of > 50% and complete responses of > 20%. Pegasys is a pegylated and pharmacologically dsitinct type of interferon. It has not been extensively studied for cutaneous lymphoma, although the first report already appeared in 1993. Most studies have been retrospective and/or were in combination with other drugs or therapies. In a recent retrospective cohort study reported in 2011 in Journal of the European Academy of Dermatology and Venereology: PEG-Interferon Alfa-2b and Ultraviolet Light Therapy in Treating Patients With Stage IB, Stage II, Stage III, or Stage IVA Mycosis Fungoides/Sezary Syndrome, NCT00724061, myelosuppression and liver toxicity occured more frequently during PEG-IFN α-2b plus PUVA treatment than during standard IFN α-2a plus PUVA therapy [77.8 vs. 50% (odds ratio 1.477) and 77.8 vs. 50% (odds ratio 1.692), respectively]. The overall response rate in the PEG-IFN α-2b plus PUVA group (89%) was significantly superior.

Several other similar studies showed comparable results. However, there are no randomized controlled studies that Caremark requires.

Taku Fujimura, Ryuhei Okuyama, Akira Hashimoto, Hiroshi Watanabe, Satoshi Nakagawa, Hachiro Tagami, Setsuya Aiba

Effective Control of Rush Progression of CD8+ Mycosis Fungoides with Pegylated Interferon, Acta Derm Venereol. 2006;86(2):161-2.

 Dummer, Reinhard Emerging drugs in cutaneous T-cell lymphomas
Expert Opinion on Emerging Drugs, Volume 10, Number 2, 1 May 2005 , pp. 381-392(12)

Y. Oyama, J. Guitart, T. Kuzel, R. Burt, S. RosenHigh-dose therapy and bone marrow transplantation in cutaneous T-cell lymphoma. 
Hematology/Oncology Clinics of North America, Volume 17, Issue 6, Pages 1475-1483, 2003.
Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003 Dec;149(6):1095-107. [67 references

Elise A. Olsen Interferon in the treatment of cutaneous T-cell lymphoma
Dermatologic Therapy Volume 16 Issue 4, Pages 311 - 321

 http://onlinelibrary.wiley.com/doi/10.1111/j.1468-3083.2011.04011.x/abstract

 

Revised 5/23/2011

Gemcitabine carboplatin for ovarian cancer

Gemcitabine and carboplatin are not FDa approved in combination for ovarian cancer; however, the combination is supported by randomized clinical trials. Carboplatin is FDA approved in other combinations. The combination is experimental because it is not FDA approved, but medically necessary. Many patients with advanced ovarian cancer will develop recurrent disease. For those patients who have recurrence of disease at least 6 months after initial therapy, the paclitaxel-platinum combination has been shown to be a superior treatment to platinum monotherapy. However, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. The efficacy and safety of an alternative regimen that does not show significant neurotoxicity were evaluated by comparing gemcitabine-carboplatin with carboplatin in platinum-sensitive recurrent ovarian cancer patients in a Gynecologic Cancer InterGroup trial of the Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group, the National Cancer Institute of Canada Clinical Trials Group, and the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group. Gemcitabine-carboplatin treatment significantly improves the PFS of patients with platinum-sensitive recurrent ovarian cancer. These results were confirmed in 2006. NCCN lists this combination for recurrent disease on p.22.

Pfisterer J, Vergote I, Du Bois A, Eisenhauer E; AGO-OVAR,; NCIC CTG; EORTC GCG. Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer.Int J Gynecol Cancer. 2005 May-Jun;15 Suppl 1:36-41.

Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück HJ, Rochon J, Zimmermann AH, Eisenhauer E; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG.
J Clin Oncol. 2006 Oct 10;24(29):4699-707.

Pfisterer J, Vergote I, Du Bois A, Eisenhauer E; AGO-OVAR,; NCIC CTG; EORTC GCG. Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer.Int J Gynecol Cancer. 2005 May-Jun;15 Suppl 1:36-41.

Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stähle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Lück HJ, Rochon J, Zimmermann AH, Eisenhauer E; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG.
J Clin Oncol. 2006 Oct 10;24(29):4699-707.

NCCN.ORG, Ovarian p.10