Cancer Treatment Today » Chemotherapy

Topotecan and Avastin for ovarian cancer – pro

M Levin, MD — Thu, 22 Nov 2012 18:46:49 +0000

Topotecan is a water-soluble, semisynthetic analogueof camptothecin that inhibits the nuclear enzyme topoisomeraseI. Topotecan has been approved by the U.S. Food and DrugAdministration (FDA) for the treatment of recurrent epithelialovarian cancer and relapsed small cell lung cancer,and has also demonstrated activity in hematologic malignancies and solid tumors including non-small cell lung, cervical, and colon cancers. In ovariancancer, topotecan has demonstrated activity in both platinum-and paclitaxel-resistant tumors, with response rates rangingfrom 12%-33%. In a randomized, phase III study,ovarian cancer patients showed similar response rates with topotecan(21%; n = 112) and paclitaxel (13%; n = 114; p = 0.138) Approximately half of all patients in both arms of thestudy had progressed on a platinum-based regimen or had relapsedwithin 6 months of completing first-line therapy. Topotecanproduced responses in 8 of 61 (13%) patients in whom paclitaxelhad failed to produce a response. Similarly, paclitaxel producedresponses in 5 of 49 (10%) patients in whom topotecan had failedto produce a response. That phase III study, and earlierphase II studies, established topotecan as an important treatment option for patients with either platinum-sensitive or platinum-refractoryrelapsed ovarian cancer. NCCN lists it as well as level 2b recommendation. It is generally assumed that fallopian tube adenocarcinoma is of ovarian tissue origin and should be treated as ovarian cancer.

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

Adjuvant chemotherapy for stage I ovarian cancer – pro

M Levin, MD — Mon, 27 Aug 2012 18:36:43 +0000

The stage of ovarian cancer is an important prognostic factor that influences survival and the choice of therapy. The quality of the surgical staging is a key determinant of treatment recommendations. Women who have undergone optimal surgical staging, including pelvic and para-aortic lymph node sampling, and have stage I disease may or may not benefit from adjuvant platinum-based chemotherapy. The results of the largest trial comparing adjuvant chemotherapy to no chemotherapy in women with early stage ovarian cancer (International Collaborative Ovarian Neoplasm Study/Adjuvant ChemoTherapy In Ovarian Neoplasm [ICON/ACTION] Trial) are controversial because:
A subgroup analysis of the ACTION Trial showed no benefit from adjuvant chemotherapy in women who underwent optimal surgical staging, but that analysis was underpowered.
The entry criteria for the ICON Trial were vague and did not reflect the standard of surgical care generally offered. The meta-analysis demonstrates that stage I patients have an improved outcome with adjuvant chemotherapy. However, an estimated 90% of women undergoing surgical resection for ovarian cancer do not undergo optimal surgical staging. If the restaging of a suboptimally staged patient reveals a more advanced disease, chemotherapy is the preferred treatment option. If reoperation confirms stage I disease, there is insufficient evidence for or against adjuvant chemotherapy. However,
NCCN lists adjuvant chemotherapy or observation alone as an option for stage Ia ovarian cancer. The most established regimen is Taxol and carboplatin.

http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf, p.7

Gynecology Cancer Disease Site Group. Elit L, Fyles A, Chambers A, Fung Kee Fung M, Covens A, Carey M. Adjuvant care for stage I ovarian cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 May 3. 33 p. (Practice guideline report; no. 4-13). [62 references]

Granulosa theca ovarian cancers: Chemo guidelines – pro

M Levin, MD — Thu, 23 Aug 2012 15:00:59 +0000

Granulosa theca tumors are rare; however, both NCCN and ESMO state chemotherapy recommendations for recurrent or metastatic disease. ESMO says: “Debulking surgery, whenever feasible, remains the most effective treatment for metastatic or recurrent granulosa cell tumors. Platinum-based chemotherapy is currently used for patients with advanced stage SCSTs or recurrent disease, with an overall response rate of 63–80%. There are limited data regarding the utility of chemotherapy in patients with persistent Sertoli–Leydig tumor, but responses in patients with measurable disease have been reported. The BEP regimen for 3–6 cycles is currently recommended for adjuvant postoperative chemotherapy and for patients with recurrent SCSTs. Taxanes demonstrated an interesting activity in SCSTs with a favorable toxicity profile [III, A].

NCCN (mentions taxol/ carboplatin) in its recommendation.

Thus, there is guideline support for Taxol/carboplatin or Avastin but not together.

N. Colombo et al, Non-epithelial ovarian cancer: ESMO Clinical Recommendations for diagnosis, treatment and follow-up Ann Oncol (2012) 23 (suppl 7): vii20-vii26.
nccn.org, ovarian 2016, LCOH – 1. OV-B 4

Continuing Avastin past progression in ovarian cancer – pro

M Levin, MD — Thu, 23 Aug 2012 03:00:22 +0000

The issue is continuing Avastin into the next line of therapy after progression. Unfortunately there is no literature specifically in ovarain cancer to support it. 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. 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 – on p. OV-D, 1.

I found that 2011 ASCO educational book favors contuning Avastin into consecutive lines of therapy but the only evidence that it can adduce is from the BRITE study, which was for colon cancer.
http://www.asco.org/ascov2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2011/zds00111000198.PDF

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 3. Nevertheless, based on the existing evidence, NCCN has now added Avastin to its list of recommended drugs for ovarian cancer and European Commission (EU) approved the use of Avastin (bevacizumab) in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin chemotherapy as a treatment for women with recurrent ovarian cancer that is resistant to platinum-containing chemotherapy 5 and in August of 2014.The EU approval was based on results of the phase III AURELIA study which involved women with recurrent, platinum-resistant ovarian cancer who received either chemotherapy or Avastin in combination with chemotherapy. Results showed that the addition of Avastin to chemotherapy gave a clinically meaningful benefit, nearly doubling the median progression free survival (PFS) from 3.4 months to 6.7 months (HR=0.38, p<0.0001).2

Food and Drug Administration (FDA) approved Avastin® in combination with chemotherapy for the treatment of women with platinum-resistant, recurrent ovarian cancer in November 2014.6

There is recent evidence that Avastin is also useful in first line therapy(1).

1.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.

2.Alessia Errico. Ovarian combination chemotherapy.Nature Reviews Clinical Oncology 11, 242 (2014)

3.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

3.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. 2902-29083.

4.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.

5. NCCN, Ovarian Cnaner, 2015

6. Avastin, Prescribing INformation 2014

Other Bibliography:

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

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

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

Read the Layperson version here.

First line Avastin for ovarian cancer – pro

M Levin, MD — Wed, 20 Jun 2012 19:30:27 +0000

At the 2010 American Society of Clinical Oncology Annual conference in Chicago, the Gynecologic Oncology Group(GOG) presented the results of the latest clinical trial for Avastin and ovarian cancer. GOG 218 (activated in October 2005) aims to randomly assign 2,000 patients in a three-arm placebo-controlled trial in which patients with stage III and IV disease receive paclitaxel and carboplatin, with or without bevacizumab (15 mg/kg every 21 days) for six courses, with a third arm continuing bevacizumab for an additional 48 weeks. Genentech, Inc., announced in February 2010 that the GOG Phase III study showed the combination of Avastin® (bevacizumab) and chemotherapy followed by maintenance use of Avastin alone increased the time women with previously untreated advanced ovarian cancer lived without the disease worsening (progression-free survival or PFS), compared to chemotherapy alone. Patients were randomly assigned to 3 treatment groups: paclitaxel 175 mg/m2 plus carboplatin area under curve (AUC) 6 cycles plus placebo maintenance; paclitaxel plus carboplatin and concurrent bevacizumab (15 mg/kg) and placebo maintenance; and paclitaxel plus carboplatin plus concurrent bevacizumab plus maintenance bevacizumab.Patients who received chemotherapy alone had a median progression-free survival of 10.3 months, compared with 11.2 months for those who received concurrent bevacizumab but placebo maintenance. GOG 218 study (Berger, ASCO 2009) only showed that, if the provider chooses to continue Avastin as maintenance, the result would be superior for the arm that included Avastin. It showed that Avastin maintenance is superior but did not answer the question of Avastin for the primary treatment itself. Women who received Avastin in combination with chemotherapy but did not continue maintenance use of Avastin did not have a longer progression free survival compared to those on chemotherapy alone. In other words, it showed that the two treatments are equivalent.

A recent 2010 abstract of ICON study presented at ESMO was supportive. Women with high-risk early or advanced ovarian cancer gained almost two months in progression-free survival (PFS) when the angiogenesis inhibitor bevacizumab (Avastin) was added to chemotherapy, results of a large international clinical trial showed. Patients who received bevacizumab in addition to carboplatin-paclitaxel chemotherapy had a median PFS of 19 months, compared with 17.3 months for those treated with chemotherapy alone. Preliminary survival data from the 1,500-patient ICON7 study show a trend toward fewer deaths in the bevacizumab group, but survival data will not be mature for another two years. This ICON7 trial was a randomized trial. The control arm of the trial was standard chemotherapy with carboplatin and paclitaxel given in the usual way for 6 cycles, 1 cycle of treatment every 3 weeks, and then no further treatment. In the research arm of the trial, patients were treated with chemotherapy and bevacizumab for 6 cycles and then received bevacizumab for a further 12 cycles of treatment, which made 18 cycles or 12 months of treatment in total. The primary endpoint for our trial was progression-free survival and the study showed that progression was delayed and occurred less frequently in patients treated with bevacizumab than in patients in the control arm.

NCCN on p. MS-8 says that unitl the data is more mature, it does not recommend routine use of Avastin to first line chemotherapy or routine maintenance. Society of Gynecologic Oncology is more supportive but not definitive. It says: ” SGO encourages patients and providers to discuss risks, benefits and costs associated with use of bevacizumab as a component of upfront treatment and maintenance therapy.”

At this point, the presented data had been peer-reviewed and published. The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. It has not been incorproated into NCCN guidelines as of January of 2012 but seems destined to be.

IRobert A. Burger, M.D., Mark F. Brady, Ph.D., Michael A. Bookman, M.D., Gini F. Fleming, M.D., Bradley J. Monk, M.D., Helen Huang, M.S., Robert S. Mannel, M.D., Howard D. Homesley, M.D., Jeffrey Fowler, M.D., Benjamin E. Greer, M.D., Matthew Boente, M.D., Michael J. Birrer, M.D., Ph.D., and Sharon X. Liang, M.D. for the Gynecologic Oncology Group ,Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer N Engl J Med 2011; 365:2473-2483December 29, 2011

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.

http://www.sgo.org/WorkArea/showcontent.aspx?id=3666

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

Read the Layperson version here.