Cancer Treatment Today » Chemotherapy

Irinotecan for brain metastases of breast and lung cancer -pro

M Levin, MD — Fri, 09 Nov 2012 15:34:51 +0000

Because irinotecan penetrates the brain-blood barrier and has an effect in primary brain cancer, there is some interest in using it for brain metastasis, especially for lung cancer and breast cancer. Most studies of irinotecan had been for brain mets of small(SCLC) and non-small cell lung cancer(NSMCLC) and not breast cancer and have had mixed results. One study reported complete responses with irinotecan-based chemotherapy for brain metastases in three patients with SCLC, parotid cancer, and esophageal adenocarcinoma. The combination of cisplatin, ifosfamide and irinotecan in treatment-naive patients with NSCLC led to an intracranial response rate of 50%. A study of temozolomide (200 mg/m²) on days 1 to 5 and irinotecan (200 mg/m²) on days 1 to 5 every 4 weeks in previously untreated patients with NSCLC brain metastases reported no responses.

There are several ongoing studies for lung cancer. For breast cancer, there is also a study: Irinotecan and Temozolomide in Treating Patients With Breast Cancer Who Have Received Previous Treatment for Brain Metastases, NCT00617539.

nccn.org, brain cancers, p.38

Chou R, Chen A, Lau D.Complete response of brain metastases to irinotecan-based chemotherapy.ONCOLOGY. Vol. 22 No. 2

Yun Oh, MD et al, Systemic Therapy for Lung Cancer Brain Metastases: A Rationale for Clinical Trials

J Clin Neurosci. 2005 Apr;12(3):242-5.ONCOLOGY. Vol. 22 No. 2

Chou R, Chen A, Lau D: Complete response of brain metastases to irinotecan-based chemotherapy. J Clin Neurosci 12:242-245, 2005. Fujita A, Fukuoka S, Takabatake H, et al: Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 59:291-295, 2000.For Lay version see here

Ajuvant chemotherapy for lung cancer – pro

M Levin, MD — Wed, 05 Sep 2012 16:25:14 +0000

Lay Summary: Adjuvant chemotherapy is now standard for lung cancer.

There is evidence to recommend platinum-based chemotherapy regimens as post-operative adjuvant therapy in the management of patients with completely resected stage II and IIIA NSCLC. Cisplatin-based treatment is preferred, although a carboplatin-based regimen can be used as an alternative if there is a contraindication to cisplatin. There is uncertainty about a benefit to patients with resected stage IB NSCLC, although adjuvant chemotherapy may still be considered in selected individuals.

A meta-analysis published in 1995 indicated that post-operative chemotherapy did not significantly reduce the risk of death in surgically resected, pathologic stage IB, II and IIIA NSCLC, although there was a trend in favour of adjuvant chemotherapy regimens that included the agent cisplatin.

ECOG 3590 and ALPI failed to demonstrate any benefit from adjuvant chemotherapy, either with or without post-operative radiotherapy. However, IALT study renewed interest in adjuvant therapy, as cisplatin-based combination chemotherapy was shown to improve relapse-free survival by 5.1%, and overall survival by 4.1% at five years.

The recent reports of NCIC CTG BR.10 and ANITA support a role for platinum-based combination chemotherapy as adjuvant therapy in resected NSCLC. Both trials demonstrated an improvement in overall survival: NCIC CTG BR.10 15% at 5 years, and ANITA 8.6% at 5 years.

A number of factors may account for the lack of benefit from adjuvant therapy in ECOG 3590 and ALPI, as compared to IALT, NCIC CTG BR.10, and ANITA. These include the potentially detrimental effect of post-operative radiotherapy, the impact of newer chemotherapy agents, and the total dose of chemotherapy delivered.

In conclusion: IALT, NCIC CTG BR.10, and ANITA provide compelling evidence in favour of adjuvant chemotherapy, although appropriate selection of patients for treatment is highlighted by the 0.8% risk in IALT of chemotherapy-related adverse events resulting in death. Both NCIC CTG BR.10 and ANITA also reported treatment-related deaths, accounting for 0.8% and 1.7% of those treated with chemotherapy, respectively.

The initial report of CALGB 9633 in 2004 indicated that adjuvant treatment with the combination of carboplatin and paclitaxel in resected stage IB NSCLC was associated with a 12% improvement in survival at 4 years. However, an update presented in 2006 demonstrated only a non-significant trend in favour of treatment at 5 years. While further analyses of CALGB 9633 are planned, the LACE meta-analysis also suggests a lack of benefit for adjuvant chemotherapy in resected stage IB NSCLC.

The Lung Tumour Group recommends routine consideration of adjuvant platinum-based combination chemotherapy in patients with fully resected stage II and IIIA NSCLC, but there is now uncertainty about its prescription in those with resected stage IB NSCLC. The magnitude of benefit of adjuvant therapy is likely proportional and dependent on the risk of relapse according to stage. There may be individuals with stage IB NSCLC with features associated with a risk of relapse similar to those with a higher stage of NSCLC. However, those high risk factors that might support selection for adjuvant chemotherapy are not defined. Adjuvant chemotherapy may still be offered to highly motivated individuals with resected stage IB NSCLC, but a discussion regarding the potential risks and harms of treatment is necessary.

Only chemotherapy regimens used in the most recent trials are evidence-based. These include the combination of cisplatin and vinorelbine as standard, as these two agents were employed in IALT, NCIC CTG BR.10 and ANITA. Cisplatin-based treatment is preferred, but in individuals with a contraindication to cisplatin, the combination of carboplatin and paclitaxel is an acceptable alternative.

References:

Douillard J, Rosell R, Delena M, Legroumellec A, Torres A, Carpagnano F. ANITA: phase III adjuvant vinorelbine and cisplatin versus observation in completely resected (stage I-III) non-small cell lung cancer patients: final results after 70-month median follow-up. J Clin Oncol 2005; 23 Suppl 16S: 624s.
Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH, for the Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000; 343: 1217-1222.
Logan DM, Lochrin CA, Darling G, Eady A, Newman TE, Evans WK and the Lung Cancer Disease Site Group. Adjuvant radiotherapy and chemotherapy in stage II or IIIA non-small cell lung cancer after complete resection. Cancer Prevent Control 1997; 1: 366-378.
Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899-909.
Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Le Chevalier T. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. Proc Am Soc Clin Oncol 2006 Part I: abstr 7008.
Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453-1461.
Strauss GM, Herndon J, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RL, Green MR. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Proc Am Soc Clin Oncol 2004; abstr 7019.
Strauss GM, Herndon JE, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RA, Vokes EE, Green MR. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. Proc Am Soc Clin Oncol 2006 Part I: abstr 7007.
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360.
Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao M, Gandara D, Kesler K, Demmy T, Shepherd F. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597.

Second line chemo for non small cell lung cancer – pro

M Levin, MD — Wed, 05 Sep 2012 15:55:51 +0000

Lay Summary: Treating with new chemo drugs after first attempt at chemo fails in non-small cell lung cancer is supported by credible evidence.

Two randomized clinical trials have been reported that addressed the issue of second-line treatment in patients with advanced NSCLC that progresses after they have received first-line platinum-based chemotherapy. Both trials used docetaxel because this agent had shown significant activity in this patient population in single-arm phase II trials. The eligibility requirements for both trials were also very similar, resulting in similar groups of patients being entered into each trial. Patients could have received more than one previous chemotherapy regimen, but 65 to 77% of the patients entered into these studies had received only one regimen. In the trial of Shepherd et al,65 previous treatment with a taxane was also an exclusion criteria. The majority of patients had a good PS (ECOG level 0 to 1 in 75 to 83% of patients), had stage IV NSCLC (80 to 90%), and were men (72 to 82%).

The first trial compared two doses of docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) to BSC in patients who were taxane-naïve but had previously been treated with a platinum-based regimen. The original design was a two-arm trial comparing docetaxel, 100 mg/m2, to BSC. The trial was halted when a 6% death rate was noted in 49 patients secondary to febrile neutropenia. Also, a median of only two cycles of therapy was delivered. The dose of docetaxel was subsequently reduced to 75 mg/m2. At this dose, the median number of cycles delivered was four, and no febrile neutropenic deaths occurred. In an analysis of all patients, both the median survival times (chemotherapy arm, 7.0 months; BSC arm, 4.6 months) and the 1-year survival rates (chemotherapy arm, 29%; BSC arm, 19%) were significantly better for patients receiving second-line docetaxel vs those receiving BSC (p = 0.047 [log rank test]). The median survival time and the 1-year survival rate for the patients treated with docetaxel, 75 mg/m2, were 7.5 months and 37%, respectively (p = 0.003 compared to BSC). The overall response rate was 7.1%, with 42.7% of patients having disease stabilization on treatment. Clinical benefit was shown in a QOL study68 in which all QOL parameters favored the docetaxel-treated patients. Specifically, a significant reduction in pain and fatigue scale scores among the docetaxel-treated patients and a reduction in the need for narcotics, nonmorphine analgesic agents, and radiotherapy were documented in this group of patients.

The second trial randomized 373 patients who had previously received platinum-containing chemotherapy to one of the three following arms: docetaxel, 100 mg/m2; docetaxel, 75 mg/m2; or a control regimen of either vinorelbine or ifosfamide (V/I). The overall response rates were 6.7 to 10.8% among patients in the two docetaxel arms vs 0.8% among patients in the V/I arm (p < 0.05). The time to progression and the progression-free survival at 26 weeks also significantly favored patients in the two docetaxel arms. Although the median survival time was not significantly different between the groups, the 1-year survival rate was significantly greater with docetaxel, 75 mg/m2, (32%) compared to V/I (19%; p = 0.025). The 1-year survival rate for patients receiving docetaxel at 100 mg/m2 was 21%.

Several of the other new agents have been studied in the second-line setting, including paclitaxel, gemcitabine, irinotecan, and vinorelbine. In general, these trials have included small numbers of patients with variable results. Response rates have ranged from 0 to 20% and median survival rates (when reported) of 4 to 8 months. No randomized trials including these other agents exist with the exception of vinorelbine, as noted above.

A recent review recommended that patients with a good PS who are experiencing disease progression after receiving platinum-based chemotherapy should be offered second-line chemotherapy. Level of evidence, good; benefit, moderate; grade of recommendation, B.

H. Cho, Y.-B. Song, I.-S. Choi, E.-H. Cho, J.-W. Choi, Y. M. Ahn, Y. H. Roh, S.-H. Nam, and B.-S. Kim
A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in Advanced Non-Small Cell Lung Cancer
Jpn. J. Clin. Oncol., January 1, 2006; 36(1): 50 – 54.

M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S – 243S.

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;

Weekly chemotherapy for lung cancer – pro

M Levin, MD — Wed, 05 Sep 2012 12:42:16 +0000

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. More recently Avastin has been shown to add to the survival benefit. Taxotere has been established as roughly equivalent to Taxol in a phase III trial.

The question is weekly dosing vs the more common three-weekly schedule.It is known that administration of Paraplatin® on either day 1 or day 8 does not alter the therapeutic index of the Gemzar®-Paraplatin® doublet for the treatment of advanced NSCLC. The use of paclitaxel plus carboplatin, administered in a novel weekly regimen, offers a safe and effective treatment option for patients with advanced lung cancer, according to research presented at the 37th Annual Meeting of the American Society of Clinical Oncology. Weekly paclitaxel and carboplatin were also the standard arm of the Tibute trial. In October, 2009 a randomized study supporting weekly dosing was reported.

Based on these studies, weekly dosing is already in wide use. I therefore do not consider it experimental.

C. Camps et al, Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial Ann Oncol (March 2006) 17 (3): 467-472

T. Sakakibara , A. Inoue , S. Sugawara , M. Maemondo , T. Ishida , K. Usui , T. Abe , M. Kanbe , H. Watanabe , Y. Saijo , and T. Nukiwa
Randomized phase II trial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with carboplatin for elderly patients with advanced non-small-cell lung cancer Annals of Oncology Advance Access published on October 8, 2009, DOI 10.1093/annonc/mdp401.
Kallab, Andre et al, A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer
Medical Oncology, Volume 22, Number 2, June 2005 , pp. 145-151(7)

Update on second lung chemotherapy of non-small cell lung cancer – pro

M Levin, MD — Wed, 29 Aug 2012 23:10:41 +0000

Treating with new chemo drugs after first attempt at chemo fails in non-small cell lung cancer is supported by credible evidence. I will discuss second line chemoing.

Two randomized clinical trials have been reported that addressed the issue of second-line treatment in patients with advanced NSCLC that progresses after they have received first-line platinum-based chemotherapy. Both trials used docetaxel because this agent had shown significant activity in this patient population in single-arm phase II trials. Several of the other new agents have been studied in the second-line setting, including paclitaxel, gemcitabine, irinotecan, and vinorelbine(Navelbine). In general, these trials have included small numbers of patients with variable results. Response rates have ranged from 0 to 20% and median survival rates (when reported) of 4 to 8 months. No randomized trials including these other agents exist with the exception of gemcitabine/vinorelbine.

ASCO in 2009 recommended: “Docetaxel, erlotinib, gefitinib, or pemetrexed is acceptable as second-line therapy for patients with advanced NSCLC with adequate PS when the disease has progressed during or after first-line, platinum-based therapy. ”

NCCN on p. NSCL 16 recommends docetaxel, premetrexed, erlotinib, platinum doublet with Avastin if erlotinib or crizotinib were given first line.
Christopher G. Azzoli, Sherman Baker Jr, Sarah Temin, William Pao, Timothy Aliff, Julie Brahmer, David H. Johnson, Janessa L. Laskin, Gregory Masters, Daniel Milton, Luke Nordquist, David G. Pfister, Steven Piantadosi, Joan H. Schiller, Reily Smith, Thomas J. Smith, John R. Strawn, David Trent and Giuseppe Giaccone American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer JCO December 20, 2009 vol. 27 no. 36 6251-6266
nccn, nonsmall cell lung cancer, 2012

M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S – 243S.

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;

Tarceva for Maintenance in Non-small Cell Lung Cancer – pro

M Levin, MD — Wed, 01 Aug 2012 17:46:57 +0000

Tarceva is FDA approved after standard chemo has failed. It is being studied for first line therapy of lung cancer instead of chemotherapy. This drug has been studied primarily in stage IV, when it has spread but recently it has been also studied, for maintenance, once treatment with chemotherapy had stopped. Studies, such as the Saturn trial, have been encouraging for maintenance and suggest prolongation of PFS but not overall survival. On April 16, 2010, the U. S. Food and Drug Administration (FDA) approved erlotinib (Tarceva) tablets for maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. NICE in 2011 did not recommend routine use of erlotinib for maintenance, because the independent Appraisal Committee felt that there was too much uncertainty about the amount of extra time or overall survival gain expected from the treatment and that based on the evidence available erlotinib was not considered value for money. On the other hand, in the USA Erlotinib is recommended as an option in the NCCN Guidelines® for maintenance therapy in advanced non-small cell lung cancer (NSCLC) based on the results of the SATURN trial.

A meta-analysis in 2013 concluded that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. This was true in both EGFR + and negative patients. As such, Tarceva maintenance is supported despite the absence of EGFR receptor testing.

Reck M: Treating Non-Small-Cell Lung Cancer First Line with Erlotinib Monotherapy in Elderly Patients: Discussion of a Case Series.
Onkologie 2007;30:515-518

F. Cappuzzo Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study The Lancet Oncology, Volume 11, Issue 6, Pages 521 – 529, June 2010 O

F. Rinaldi et al, , NICE guidance on erlotinib for the maintenance treatment of non-small-cell lung cancer The Lancet Oncology, Volume 12, Issue 8, Pages 728 – 730, 2011

NCCN Clinical Practice Guidelines in Oncology®: Non-Small Cell Lung Cancer V.1.2012, NSCL-13

Yiqian Liu et al ,Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review
PLOS Published: March 21, 2013 • http://dx.doi.org/10.1371/journal.pone.0059314

Read the Layperson version here.

Tarceva and Avastin for lung cancer – pro

M Levin, MD — Thu, 21 Jun 2012 01:26:34 +0000

After encouraging initial reports, a phase III trial found a combination of Avastin and Tarceva did not extend lung cancer patients’ survival, Roche Holding AG and Genentech was cited by Reuters as saying on Tuesday October 7, 2008. The trial included 120 patients. One group was treated with standard chemotherapy consisting of Taxotere® (docetaxel) plus Alimta® (pemetrexed), a second group was treated with Taxotere/Alimta/Avastin, and the third group was treated with Avastin plus Tarceva.

However, addition of bevacizumab to erlotinib as first-line therapy yielded a significantly extended progression-free survival (PFS) in patients with advanced EGFR-mutation–positive non–small-cell lung cancer (NSCLC), according to a new phase II study. Results from the randomized, open-label trial were presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

The European Commission has approved the use of Avastin® (bevacizumab) in combination with Tarceva® (erlotinib) for the first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR)-activating mutations.

The pivotal phase II JO25567 study showed a statistically significant 46 percent relative reduction in the risk of disease progression or death (median PFS: 16.0 months versus 9.7 months; [HR]=0.54, p=0.0015) for people treated with the combination of Avastin plus Tarceva compared to Tarceva alone.1 Avastin and Tarceva each target pathways which are known to be key drivers in the development and growth of tumours. The beneficial effect of Avastin plus Tarceva is supported by results of other clinical studies which showed the combination was effective and tolerable.

Seto T et al. Lancet Oncol. 2014; 15(11): 1236-44

Herbst RS et al. Lan Oncol. 2011; 377(9780): 1846-54

Reck M: Treating Non-Small-Cell Lung Cancer First Line with Erlotinib Monotherapy in Elderly Patients: Discussion of a Case Series.
Onkologie 2007;30:515-518

O. Belvedere and F. Grossi
Lung Cancer Highlights from ASCO 2005
Oncologist, January 1, 2006; 11(1): 39 – 50.

Fehrenbacher L, O’Neill V, Belani CP, et al. A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer. Proceedings of the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2-6, 2006. Abstract # 7062.