NCCN supports second line use of Avastin alone or in combination – on p. OV-D, 1.

In terms of putting the two drugs together, only one recently completed study addresses this question. Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02).

It concluded that a weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted.

McGonigle KF, Muntz HG, Vuky J, Paley PJ, Veljovich DS, Greer BE, Goff BA, Gray HJ, Malpass Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. Cancer. 2011 Aug 15;117(16):3731-40.

Miller DS, Blessing JA, Lentz SS et al. Phase II evaluation of three-day topotecan in recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study. Presented at the 33rd Annual Meeting of the Society of Gynecologic Oncologists, Miami, FL, March 16–20, 2002.

Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. J Clin Oncol. 2010;28:abstract LBA1, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Available at: http://meeting.ascopubs.org/cgi/content/abstract/28/18_suppl/LBA1

Monk B, Han E, Josephs-Cowan C, et al. Salvage Bevacizumab (rhuMAB VEGF)-based Therapy after Multiple Prior Cytotoxic Regimens in Advanced Refractory Epithelial Ovarian Cancer. Gynecologic Oncology. 2006; 102: 140-144.

Robert A. Burger, Experience With Bevacizumab in the Management of Epithelial Ovarian Cancer, Journal of Clinical Oncology, Vol 25, No 20 (July 10), 2007: pp. 2902-2908

Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.

For Lay version see here

The Avastin application to the FDA was based on a Phase II clinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination with irinotecan chemotherapy. When Avastin was evaluated as a single agent, the study showed that at six months 43 percent of patients lived without their disease advancing, as defined by progression-free survival (PFS). In the study, 28 percent of patients responded to Avastin, meaning tumors decreased in size by at least 50 percent. Patients receiving Avastin had a median overall survival of 9.3 months, a secondary endpoint in the study. Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastin studies. The most common severe (Grade 3 or greater) toxicities in the Avastin-only arm were hypertension (8 percent) and convulsion (6 percent). There were two deaths associated with adverse events in the Avastin-only arm. These data, along with those from the combined Avastin and irinotecan study arm, were presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).

Avastin is now FDA indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

A. Reardon, Patrick Y. Wen Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncol 2005;7:369.

Cloughesy T, et al “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)” J Clin Oncol 26: 2008; May 20 suppl; Abstract 2010b.

nccn.org, brain cancers, p.38

NCCN does recommend it for salvage therapy but the most recent Alberta guideline does not.

Micha JP, ET AL, Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. : Gynecol Oncol. 2006 Feb;100(2):437-8. Epub 2005 Oct

Abraxane, Prescribing information

NCCN.ORG, Ovarian Cancer 2912

Alberta Provincial Gynecologic Oncology Tumour Team. Epithelial ovarian, fallopian tube, and primary peritoneal cancer. Edmonton (Alberta): Alberta Health Services, Cancer Care; 2010 Jul. 19 p. (Clinical practice guideline; no. GYNE-005). [104 references]

Patients with ovarian cancer that has recurred or progressed following prior therapies, have unfavorable long-term outcomes with standard therapies. Although additional chemotherapy can be used to treat these patients, they often have minimal anti-cancer responses as well as side effects from treatment. Initial study of Avastin focused on this unfavourable group. Researchers from California conducted a study to evaluate the effectiveness of Avastin for the treatment of recurrent ovarian cancer. This trial included 33 patients who had received extensive prior chemotherapy. The majority of patients were treated with Avastin as a single agent. This is the 3rd positive phase II trial. The previous trials included Avastin with metronomic cyclophosphamide and one with a taxane. A phase III trial, however, was stopped by Genetech when an unexpected 11% of participants developed bowel perforations. The debate about why this happened and how it was related to the patient characteristics still has not been resolved.

Patients with ovarian cancer that has recurred or progressed following prior therapies, have unfavorable long-term outcomes with standard therapies. Although additional chemotherapy can be used to treat these patients, they often have minimal anti-cancer responses as well as side effects from treatment. Initial study of Avastin focused on this unfavourable group. Researchers from California conducted a study to evaluate the effectiveness of Avastin for treatment of recurrent ovarian cancer. This trial included 33 patients who had received extensive prior chemotherapy. The majority of patients were treated with Avastin as a single agent. This is the 3rd positive phase II trial. The previous trials included Avastin with metronomic cyclophosphamide and one with a taxane. A phase III trial, however, was stopped by Genetech when an unexpected 11% of participants developed bowel perforations. The debate about why this happened and how it was related to the patient characteristics still has not been resolved. Nevertheless, based on the existing evidence, NCCN has now added Avastin to its list of recommended drugs for ovarian cancer.

NCCN supports second line use of Avastin alone or in combination , but the only combination that it mentions specifically is gemcitabine/carboplatin/bevacizumab and carboplatin liposomal doxorubicin with or without Avastin. The discussion of the guidelines at MS-14 (makes it clear that this is the correct interpretation of teh OV-E page. Carboplatin plus gemcitabine with or without bevacizumab has recently been published as the OCEANS trial (Aghajanian et al). This study showed a higher response rate and a slightly prolonged time to recurrence with the addition of bevacizumab. However, overall survival was identical. Therefore, this regimen has received only a category 2B level of evidence in NCCN guidelines.

Perren T, Swart AM, Pfisterer J, et al: ICON7: A phase III randomized gynaecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab versus chemotherapy alone in women with newly diagnosed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Program and abstracts of the 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract LBA4.

Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. J Clin Oncol. 2010;28:abstract LBA1, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Available at: http://meeting.ascopubs.org/cgi/content/abstract/28/18_suppl/LBA1

Monk B, Han E, Josephs-Cowan C, et al. Salvage Bevacizumab (rhuMAB VEGF)-based Therapy after Multiple Prior Cytotoxic Regimens in Advanced Refractory Epithelial Ovarian Cancer. Gynecologic Oncology. 2006; 102: 140-144.

Bidus MA, Webb JC, Seidman JD, et al. Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms.Gynecologic Oncology. 2006;May 11

Cohn DE, Valmadre S, Resnick KE, et al. Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecologic Oncology. 2006;March 7

Robert A. Burger, Experience With Bevacizumab in the Management of Epithelial Ovarian Cancer, Journal of Clinical Oncology, Vol 25, No 20 (July 10), 2007: pp. 2902-2908

Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.

Cohn DE, Valmadre S, Resnick KE, et al. Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecologic Oncology. 2006;March

Daniela Luvero et al, Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther Adv Med Oncol. 2014 Sep; 6(5): 229239 7;

NCCN Ovarian Cancer OV-C, 6 of 8, 2019

In January 2005, the U.S. Food and Drug Administration (FDA) approved the chemotherapy drug Abraxane, a new formulation of paclitaxel, for treating advanced (metastatic) breast cancer. The approval is for second-line therapy—after another chemotherapy regimen has been used and has stopped working.

Paclitaxel belongs to a class of chemotherapy drugs called taxanes (Taxol (chemical name: paclitaxel) and Taxotere (chemical name: docetaxel) are the most widely known). But taxanes cause serious side effects, including low white blood cell counts (neutropenia), weakness, and infection. Paclitaxel has to dissolve so it can enter the bloodstream. But paclitaxel does not dissolve in water. Up unti now it has been dissolved in Cremophor, a derivative of castor oil. However, Cremophor makes paclitaxel more toxic and more difficult to tolerate. In order to avoid having serious allergic reactions to Cremophor, women must receive steroids before they receive Taxol.

Abraxane provides a new way to make paclitaxel dissolve in water. Instead of Cremophor, Abraxane uses albumin, a natural protein found in the body. A tiny bit of paclitaxel is suspended in each albumin particle. Because albumin is natural to the body, there is no need to take steroids before receiving Abraxane. And since taking Abraxane does not require taking pre-medication to reduce the risk of an allergic reaction, an Abraxane treatment averages 30 minutes compared with three hours for Taxol. In a Phase III research study, Abraxane was compared directly to Taxol in 454 women. The results of a Phase III trial show that cancers responded better to Abraxane than Taxol and stayed under control longer.

Avastin (chemical name: bevacizumab) is an antiangiogenesis medicine that has been approved by the U.S. Food and Drug Administration (FDA) to treat advanced cancer of the colon or rectum when combined with chemotherapy.

Researchers have studied Avastin as a treatment for women with advanced breast cancer. The Eastern Cooperative Oncology Group presented results of that research, called Trial E2100, at both the American Society of Clinical Oncology annual meeting and the San Antonio Breast Cancer Symposium in 2005. They found that women who received Avastin plus the chemotherapy drug Taxol (chemical name: paclitaxel) had a longer time before their cancer worsened than women who got only Taxol. Compared to Taxol alone, Avastin plus Taxol reduced the risk of the cancer progressing by 50%.

It is possible to view Abraxane as a totally new drug or as a different form of palcitaxel. The answer to the above question will depend on which of the two possibilities one affirms. In practice, a study is ongoing:
CA023 A Phase II study of Abraxane with Avastin for Metastatic Breast Cancer. This is a multi-center, open-label, randomized Phase II study in previously untreated patients with metastatic breast cancer to evaluate the antitumor activity and safety of weekly dose-dense ABI-007 (Abraxane) compared to a 2-weekly regimen vs the standard 3-weekly infusion. All patients will also receive concurrent bevacizumab.

The issue is clouded by the recent withdrawal of the FDA indication for Taxol and Avastin.

NCCN 2011 NIV-N,1 lists Abraxane as a recommended first line single drug for metastatic breast cancer.
In as much as NCCN reflects current literature and consensus, Abraxane should be considered medically necessarybased on the current peer-reviewed literature.

However, the combination of Xeloda and Abraxane is not listed by NCCN. A phase II trial(Swartzberg et al) was encouraging in that inerim results of a small study showed:
■Complete responses (complete disappearances of detectable cancer) were achieved in nearly 9% of patients.
■Partial responses (partial regression of cancer) were achieved in 44% of patients.
■Disease stabilization was achieved in 32.4% of patients.
■Overall, this treatment regimen was generally well tolerated.

Unfortunately more study would be required and Abraxane and Xeloda combination should not be routinely used at this time.

Furlanetto J, Jackisch C, Untch M, et al. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer. Results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Mar 17

Miller KD et al.Effect of adding bevacizumab to paclitaxel on progression-free survival of patients with previously untreated metastatic breast cancer; results of ECOG 2100 trial. San Antonio Breast Cancer Symposium, 2005. Abstract 3.

M. R. Green et al, Abraxane®, a novel Cremophor®-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer Annals of Oncology 2006 17(8):1263-1268

Link J, Waisman J, Jacobs C. Bevacizumab (Avastin) and albumin bound paclitaxel (Abraxane) treatment in metastatic breast cancer. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1095.

Ran S, Biven C, Trieu V, Desai N. Synergistic effect of albumin-bound paclitaxel (Abraxane) and anti-VEGF-A antibody (avastin) on growth of orthotopic MDA-MB-231 breast tumors as well as lymphatic and pulmonary metastases. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1094

Swartzberg L, et al. Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC): interim results. Proceedings from the 2006 Annual San Antonio Breast Cancer Symposium. December 2006. Abstract 1096.

Glioblastoma is a disease for which there were few options available until recently. The past several years brought several new potentially promising treatments and one, Temodar, has been FDA approved for this indication. One of these promising approaches is Avastin and irinotecan. Stark-Vance recently reported that, among 21 patients with recurrent malignant glioma treated with bevacizumab plus irinotecan (Camptosar®; Pfizer Pharmaceuticals), one patient achieved a complete response, eight achieved partial responses, and 11 achieved stable disease. Overall, the regimen was reported as well tolerated, although two deaths occurred on treatment, including one patient with an intracranial hemorrhage and one patient with bowel perforation. A formal, single-arm phase II study of bevacizumab plus irinotecan is being performed at the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center for patients with recurrent malignant glioma. Preliminary analyses of results of this trial reveal that this regimen is well tolerated among malignant glioma patients and is associated with a highly exciting rate of radiographic response. Further investigation of the regimen of bevacizumab plus irinotecan is planned. Currently there are 11 sites nationally to participate in the pivotal clinical trial of bevacizumab and irinotecan (Avastin) in recurrent glioblastoma; this combination has been reported to shrink tumors in 63% of patients with recurrent glioblastoma in one small study.There are also other phase II trials combining Avastin with carboplatin, etoposide and other drugs. In late November 2007, Genetech announced preliminary results of its randomized phase II study with two arms, Avastin vs. Irinotecan/Avastin. The latter arm has a higher TTP and response rate. However, when updated at 2008 ASCO, the Avastin arm had survival of 9.2 months in a bevacizumab-alone group versus 8.7 months with irinotecan, The study is ongoing. There are no reported phase III trials or guideline recommendations for Avastin or Camptosar + Avastin. Avastin alone is in an ongoing phase II trial.

NCCN lists the combination with irinotecan and footnotes it to a 2007 phase II trial. Based on the NCCN recommendation, irinotecan/avastin should not be considered any longer to be investigational, even in the absence of phase III trials; however, because there are no phase III trials, individual insurers may be justified in rejecting NCCN recommendation.

Regarding Avastin alone:

Genentech, Inc. (NYSE: DNA) announced in November 2008 that the company submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for Avastin® (bevacizumab) as a therapy for people with previously treated glioblastoma. If accepted by the FDA, the application would be considered for an accelerated approval that allows provisional approval of medicines for cancer or other life-threatening diseases based on preliminary evidence suggesting clinical benefit.

The Avastin application is based on a Phase II clinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination with irinotecan chemotherapy. When Avastin was evaluated as a single agent, the study showed that at six months 43 percent of patients lived without their disease advancing, as defined by progression-free survival (PFS). In the study, 28 percent of patients responded to Avastin, meaning tumors decreased in size by at least 50 percent. Patients receiving Avastin had a median overall survival of 9.3 months, a secondary endpoint in the study. Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastin studies. The most common severe (Grade 3 or greater) toxicities in the Avastin-only arm were hypertension (8 percent) and convulsion (6 percent). There were two deaths associated with adverse events in the Avastin-only arm. These data, along with those from the combined Avastin and irinotecan study arm, were presented earlier this year at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).
NCCN has incorporated this regimen into its guideline.

WIth carboplatin: A 2012 study by Readon found that the addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

 Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncol 2005;7:369.

Cloughesy T, et al “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)” J Clin Oncol 26: 2008; May 20 suppl; Abstract 2010b.

nccn.org, brain cancers, p.38

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.

Olson JJ, Fadul CE, Brat DJ, et al. Management of newly diagnosed glioblastoma: guidelines, development, value and application. J Neurooncol. 2009;93:1-23.

Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.J Neurooncol. 2012 Mar;107(1):155-64.

Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether docetaxel, prednisone and bevacizumab are more effective than docetaxel and prednisone in treating prostate cancer.

Findings from a recent phase II trial have shown that a combination of provange and avastin may be beneficial for patients with prostate cancer. The study population consisted of 22 patients who had androgen depended prostate cancer and was having increasing levels of PSA. All patients had undergone previous definitive treatment either in the form of radiation therapy or surgery. All patients received a combination of APC8015 (provenge) in combination with avastin. The treatment was continued until patient had either disease progression or intolerable side effects. The FDA followed ODAC’s recommendation against Provenge.

Out of 22 patients 21 were evaluable for end points of the study. The median PSA doubling time in these patients was 6.7 months and median time on treatment was 12.7 months. No patients on the study had objective disease progression (onset of measurable bone or soft tissue metastasis). Four patients could not continue with the study due to toxicities and were removed from the study.

The results of a CALGB trial indicate that Avastin™/Taxotere® and estramustine can be administered safely and effectively in patients with hormone-refractory prostate cancer. The median age of the patients in this trial was 73 years, and the median PSA at study entry was 128 ng/dl. Of the 79 evaluable patients treated, 45% had measurable soft tissue lesions while 85% had a positive bone scan. Thromboembolic events (6%) were reported in 5 patients; one patient succumbed to a pulmonary embolus. Measurable disease responses were observed and 42% of patients, while 79% of patients evidenced a >50 percent PSA decline. The median time to progression has not yet been reached, and the median survival reported was approximately 20 months. The rate of thromboembolic events with this combination appears to be similar to what has been reported for other estramustine/taxane studies. Avastin alone is in a phase II trial.

There is an ongoig randomized phase III trial that is studying docetaxel, prednisone and bevacizumab to see how well they work compared to docetaxel and prednisone in treating patients with prostate cancer that did not respond to hormone therapy. Other combination trials are also being launched.

http://www.slhn-lehighvalley.org/body.cfm?id=700#CTSU90401

http://www.clinicaltrials.gov/ct/gui/show/NCT00089609

Picus J, Halabi S, Rini B, et al. The use of bevacizumab (B) with Taxotere (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006. Proceedings from the 39th annual meeting of the American Society of Clinical Oncology, May 2003.Abstract 1578.

nccn.org, prostate

Adjuvant chemotherapy for Stage II colon cancer is controversial but the field until recently was moving away from it. A recent study is reporting again that it may be beneficial.

Recent guidelines make it optional rather than recommended.

Recent guidelines make OncotypeDx Colon optional rather than recommended. An ASCO panel collaborating with the Cancer Care Ontario Practice Guideline Initiative reviewed randomized controlled trials and other relevant studies from the literature through May 2003. This meta-analysis found no evidence in stage II patients of statistically significant improvement in survival with adjuvant chemotherapy.
The guidelines acknowledge that the same relative benefit probably results from adjuvant therapy for patients at both stages II and III, but that the number of patients studied in most trials is too small to detect and quantify absolute survival benefits from adjuvant therapy in stage II disease. To detect a survival difference of 2% between treatment and control groups of a trial, a sample size of 9,680 per group would be needed (90% power with a significance level of .05).
“Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease,” the authors write. “The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.” This is also the conclusion of the NCCN and other guidelines.

The QUASAR study data was used to validate Oncotype DX test, which became avalilble in early 2010. Based on data from the nearly 3,300 patients in development and validation studies, the Oncotype DX Colon Cancer Assay was thought to deliver information that can be used to help make decisions about adjuvant therapy. The assay provides an individualized Recurrence Score, which gives the oncologist the patient-specific information to help decide which of stage II colon cancer patients should be most appropriately considered for post-surgical chemotherapy. Supporting the original QUASAR study, additional results from a second clinical validation study of stage II colon cancer patients enrolled in CALGB 9581 further confirmed that the Recurrence Score result improves the ability to differentiate higher from lower recurrence risk beyond conventional factors, such as tumor grade, the number of nodes examined, and lymphovascular invasion. There is also support from several smaller retrospective analyses.

The Recurrence Score is based upon the quantitative expression of the 7 cancer genes, normalized to the 5 reference genes. The Recurrence Score includes 7 genes identified as consistently and significantly associated with recurrence-free interval (RFI) in the 1,851 patients from the development studies. These genes include the cell cycle group (Ki-67, MYBL2, C-MYC), the stromal group (FAP, INHBA, BGN) and GADD45B. The pre-specified Recurrence Score gene panel was validated in 1,436 stage II colon cancer patients with tissue from the QUASAR trial. To my knowledge, no professional group or guideline has yet recommended OncotypeDx. NCCN COl-3, 2018 does not recommend it.

A recent study by Dawod et al showed that that the decision to prescribe adjuvant chemotherapy was changed in 27% of patients with this test, but not whether that change was ultimately beneficial or not.

QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet Oncology. 2007;370:2020-2029.

Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004 Aug 15;22(16):3408-19. [45 references]
NCCN.ORG, Colon Cancer 2018

Kerr D, Gray P, Quirke P, et al. A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. Journal of Clinical Oncology 2009;27:15s, Abstract #4000.

Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 2016 Sep 19. doi: 10.1016/S1470-2045(16)30172-3

Figueredo A, Coombes ME, Mukherjee S. Adjuvant Therapy for completely resected Stage II Colon Cancer. Cochrane Database of Systematic Reviews 2008, Issue 3.

Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27(6):872-7

Venook A, Niedzwiecki D, Lopatin M, et al. Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581. Presented at: American Society of Clinical Oncology; June 2011; Chicago, IL.
Mohammed Adam Ibrahim Dawod, Jane Sze Yin Sui, Deirdre Kelly, Lynda M. McSorley, Claire Brady, Richard Bambury, Seamus O’Reilly, Emmet J Andrews, Morgan McCourt, Michael O’Riordain, Kevin J. Murray, Brian Waldron, Michael William Bennett, Ken Feeley, and Derek Gerard PowerClinical utility of Oncotype DX in early stage colon cancer. Journal of Clinical Oncology 2017 35:15_suppl, e15076-e15076

Meropol N, Lyman GH, Chien R. Use of a multigene prognostic assay for selection of adjuvant chemotherapy in patients with stage II colon cancer: Impact on quality-adjusted life expectancy and costs. Poster presented at the American Society Clinical Oncology Gastrointestinal Cancers Symposium; San Francisco, CA; January 2011.

Palliative chemotherapy for metastatic lung cancer is now standard. Platinum-based combinations were the first regimens to convincingly have an impact on survival and have been the standard of care in NSCLC. A European study showed that gemcitabine/cisplatin was essentiall equivalent to paclitaxel and a platin and the former became standard in Europe whereas the latter is most often used in the USA. Docetaxel has been shown to be equivalent to paclitaxel in phase III studies.A randomized comparative study showed that paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non–small-cell lung cancer (NSCLC)are equivalent and equally tolerated.

More recently Avastin has been shown to add to the survival benefit. Bevacizumab (Avastin®) is a humanized recombinant antibody to vascular endothelial growth factor-A (VEGF-A). VEGF-A bound to bevacizumab cannot bind to or activate VEGF receptors (VEGF-R) on vascular endothelial and other cells. Biological consequences include inhibition of angiogenesis (growth of new blood vessels) in tumors. Bevacizumab combined with intravenous fluorouracil-based chemotherapy is indicated as first- or second-line therapy for advanced or metastatic colon or rectal cancers.

An Eastern Cooperative Oncology Group (ECOG) multicenter RCT (E2100) on paclitaxel with (n=341) versus without (n=339) bevacizumab as first-line therapy for inoperable metastatic disease found that it was of value. The first interim analysis reported statistically significant improvement in overall response rate (ORR), PFS, and OS. The second interim analysis also found statistically significant improvement in ORR (30% versus 14%, p<0.0001) and PFS (11.4 versus 6.1 months; p<0.0001), but effects on OS were no longer statistically significant (28.4 versus 25.2 months; p=0.12). Avastin has subsequently gained approval for breast cancer in the US and EU, and for first-line NSCLC in the US.

A second large multicenter study, AVAIL, has shown that adding bevacizumab (Avastin, Genentech) to chemotherapy improves survival in patients with advanced non–small-cell lung cancer (NSCLC). This latest study was conducted in Europe and used a different chemotherapy regimen, gemcitabine and cisplatin, the European standard, from that used in the first trial, which was carried out in the United States. But the results from both trials were similar — adding bevacizumab significantly improved progression-free survival (PFS).

In breast cancer where Avastin was FDA approved, the role of Avastin is beng re-evaluated following reports of a new study showing no benefit in first line. One can question the true benefit of bevacizumab for lung canner as well, pointing out that the improvement in median PFS over control was only 2 weeks. On the other hand, the drug increases the risk for adverse events and costs thousands of dollars. However, the same is true of the now accepted in the USA paclitaxel and carboplatin + Avastin. In the USA paclitaxel and carboplatin is now standard and Avastin was approved by the FDA in a “a first-line treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer in combination with platinum-based chemotherapy”. NCCN now recommends bevacizumab with “chemotherapy” without defining is solely as being platin based.

NCCN has first and second line therapy recommendations, both single agents and in combination.  For third line therapy NCCN recommends  Docetaxel, Pemetrexed, Erlotinib or Docetaxel, Pemetrexed, Erlotinib, Gemcitabine. Therefore, there are standard options and a clinical study is not standard of care.

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small Cell Lung Cancer, Focused Update of Recommendation A6 published in Journal of Clinical Oncology, Vol 29, No 28 (October 1), 2011:3825-3831

nccn.org, NSCL Cancer, NSCL-F 2017

R. Milroy New American College of Chest Physicians Lung Cancer Guidelines*: An Important Addition to the Lung Cancer Guidelines Armamentarium
Chest, September 1, 2007; 132(3): 744 – 746.

Lung Cancer Disease Site Group. Chemotherapy in stage IV (metastatic) non-small cell lung cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jan. 22 p. (Practice guideline report; no. 7-2). [28 references]

Volk V et al, Weekly carboplatin in combination with weekly paclitaxel in the treatment of metastatic non-small cell lung cancer: a single center 10-year experience.Spport Care Cancer. 2016 May;24(5):2119-2128. 

The combination of Abraxane (albumin bound paclitaxel) and Paraplatin® (carboplatin) and Avastin (bevacizumab) provides responses or disease stabilization in over 75% of patients with chemotherapy-naïve, advanced non-small cell lung cancer (NSCLC). These results were presented at the 2006 annual Chemotherapy Foundation Symposium.

Abraxane consists of the active ingredient paclitaxel, which is found in Taxol® and its generic equivalents. However, in the formulation of Abraxane, paclitaxel is delivered in a suspension of albumin particles, offering several advantages to Taxol and its generic equivalents, in which polyethoxylated castor oil (Cremophor EL) is used as the solvent for paclitaxel.

Results from previous studies have indicated that single-agent Abraxane is well tolerated and produces significant responses in patients with previously un-treated NSCLC. Researchers continue to evaluate Abraxane in combination with other chemotherapy agents, as well as targeted therapies for the treatment of NSCLC.

Results presented at the Chemotherapy Foundation Symposium were from a phase II open-label clinical trial including 50 chemotherapy-naïve advanced NSCLC patients. Treatment included Abraxane (300 mg/m2) and Paraplatin AUC 6 plus Avastin every 3 weeks. Avastin was not continued beyond 4-6 cycles of chemotherapy.

Confirmed responses were achieved in 26% of patients.
Disease stabilization was achieved in an additional 48% of patients.
Hemoptysis occurred in 6% if patients with 1 fatal event.
The researchers concluded that the treatment combination consisting of Abraxane, Paraplatin and Avastin provides responses or disease stabilization in a vast majority of patients with chemotherapy-naïve, advanced NSCLC. These results provide further evidence that Abraxane in combination with other agents is promising in the treatment of NSCLC.

Abraxane is in phase II studies with carboplatin in lung cancer.

Reynolds C, et al. Nab-Paclitaxel/Carboplatin/Bevacizumab in Advanced Non-Squamous NSCLC. Proceedings of the Chemotherapy Foundation Symposium XXIV. New York, New York. November 12, 2006.

nccn.org, lung cancer