Cancer Treatment

Gemcitaibne for non-small cell lung cancer in second line

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.

NCCN does not list Gemzar for second-line therapy(NSCL-16). I did find a recent guideline that focuses specifically on the role of gemcitabine: Use of Gemcitabine in Non-Small Cell Lung Cancer
Practice Guideline Report # 7-8 (Version 2.2002) by Ellis P, Mackay JA, Evans WK, and the Lung Cancer Disease Site Group. It says: "There is currently no evidence from randomized clinical trials that second-line chemotherapy with gemcitabine is associated with any improvement in survival. The routine use of gemcitabine as second-line chemotherapy cannot be recommended. Therefore, Gemzar alone is not supported by credible scientific evidence published in peer-reviewed medical literature generally and recognized by the relevant medical community. NCCN recommends for second line: docetaxel, premetrexed or erlotinib.

nccn.org, nonsmall cell lung cancer,

Use of Gemcitabine in Non-Small Cell Lung Cancer
Practice Guideline Report # 7-8 (Version 2.2002) by Ellis P, Mackay JA, Evans WK, and the Lung Cancer Disease Site Group. 

 

CT staging of non-small cell lung cancer

In non-small cell lung cancer (NSCLC), the determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients. The stage of disease is based on a combination of clinical factors (i.e., physical examination, radiology, and laboratory studies) and pathological factors (i.e., biopsy of lymph nodes, bronchoscopy, mediastinoscopy, or anterior mediastinotomy). CT of the chest is usually considered sufficient for body staging. The CT scan should extend inferiorly to include the liver and adrenal glands and this is the NCCN recommendation.

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC but without neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. Whether the improved detection rate of MRI translates into improved outcome remains unknown and CT of thte brain is considered fully acceptable. For stage III it is certainly the standard of care.

For PET scanning, see here

Webb WR, Gatsonis C, Zerhouni EA, et al.: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178 (3): 705-13, 1991.

Toloza EM, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 123 (1 Suppl): 137S-146S, 2003. 

Gould MK, Kuschner WG, Rydzak CE, et al.: Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 139 (11): 879-92, 2003.

Alimta and Avastin for lung cancer

Alimta and cisplatin are FDA approved for second and first line therapy of lung cancer.  Carboplatin can be substituted for cisplatin based on studies that showed equivalent therapeutic results and carboplatin is better tolerated (NCCN, 2011, p.MS-29). At this time, Alimta is FDA approved, as follows:  ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is not indicated for treatment of patients with squamous cell non-small cell lung cancer. ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. More recently, NCCN changed the wording of its recommendations from specific chemo regimens with Avastin to "chemotherapy with Avastin". This has been widely interpreted to include premetrexed based regimens or other regimens but NCCN did not list these regimens in its section "Systemic Therapy". Unfortunately NCCN is not clear in its descriptive section either. Thus, NCCN is not definitive on whether it considers Alimta and Avastin to be appropriate. Uptodate, on the other hand, considers combination of carboplatin/Alimta/Avastin standard of care for first-line chemotherapy regimen in metastatic NSCLC.  FDA indication is: "Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel."

I therefore conclude that Alimta/carboplatin/Avastin is not established as medically necessary at this time. The combination is under trial.

There are several trials that are looking at Avastin in combintion with Alimta based regimens.

1.Alimta and Avastin are currently in a phase II study:  Pemetrexed Plus Bevacizumab in Non Small Cell Lung Cancer, NCT00741221. There are also ongoing phase II studies that include platins.

 2.NCT00234052 -- Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer. This study is ongoing but not recruiting participants.

3.. NCT00614822 -- A Phase II Trial of Carboplatin, Bevacizumab and Pemetrexed in Advanced Non-Small Cell Lung Cancer. This study is recruiting participants.

4. NCT00762034 -- Randomized, Open-Label, Phase 3 Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Non-squamous Non-Small Cell Lung Cancer. This study is recruiting participants.   

5.Further studies are necessary to determine whether carboplatin/Alimta/Avastin is superior to standard regimen carboplatin/paclitaxel/Avastin.  This is being investigated in a randomized phase III study NCT00762034 which also included the maintenance treatment.  This study is recruiting participants.          

 Scagliotti G, et al  Phase III Study of Pemetrexed Plus Cisplatin Versus Gemcitabine Plus Cisplatin in Chemonaive patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC). Proceedings from the International Association for the Study of Lung Cancer meeting. 2007. Abstract #PRS-03.

NCCN Practice Guidelines in Oncology. v.2.2010. Non-Small Cell Lung Cancer. NSCL-14, 2011

 Lilenbaum RC. Initial systemic chemotherapy for advanced non-small cell lung cancer. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2009.

  Einhorn, LH. First-line chemotherapy for non-small-cell lung cancer: is there a superior regimen based on histology?. J Clin Oncol 2008; 26:3485.

 Azzoli CG, Baker S Jr, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G; American Society of Clinical Oncology. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009 Dec 20;27(36):6251-66.

Gronberg B, et al. A Phase III Study by the Norwegian Lung Cancer Group: Pemetrexed + Carboplatin vs. Gemcitabine + Carboplatin as First-Line Chemotherapy in Stage IIIB/IV Non-Small Cell Lung Cancer. Proceedings from the International Association for the Study of Lung Cancer meeting. 2007. Abstract A3-04.

Zinner RG, Fossella FV, Gladish GW, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of ad-vanced nonsmall cell lung cancer. Cancer. 2005 Dec 1;104(11):2449-56.        

Nexavar in non-small cell lung cancer

Nexavar is an orally active, multi-kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma. Nexavar has wide anti-tumor effects and has been tested in a variety of other cancers, including prostate and melanoma.In a pilot study, 6 patients with recurrent NSCLC were treated with single agent Nexavar®. This study demonstrated single agent activity with partial responses in two patients and stable disease in two others. This led to a larger study involving 52 patients with relapsed NSCLC treated with single agent Nexavar. In this study there were no partial or complete remissions, but 59% had stable disease. The median progression-free survival was 2.7 months and the overall survival was 205 days. There were no grade IV toxicities. 8% of patients in this study had bleeding. Three patients in this study had Nexavar discontinued due to hand-foot syndrome, elevated lipase and myocardial infarction. A quality of life study concluded that Nexavar did not adversely impact patient-reported outcomes in function and symptom response during treatment.

The results of a phase I clinical trial evaluated the combination of Nexavar and Iressa® (gefitinib) for the treatment of 32 patients with refractory or recurrent NSCLC were presented at the 2005 ASCO meeting. It was concluded that Nexavar and Iressa was a safe combination for treating patients with NSCLC.

In another phase I/II clinical trial, Nexavar was combined with Taxol® (paclitaxel) and Paraplatin® (carboplatin) for treatment of 15 patients with advanced progressive NSCLC. The partial response rate was 29% and 50% had stable disease for a disease control rate of 79%. The median duration of response was 25 weeks and progression-free survival was 7.5 months. There appeared to be no increase in toxicity from adding Nexavar to Taxol and Paraplatin in this study.

Recently, however, Nexavar was dropped from an ongoing trial. Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals have stopped a late stage trial of their cancer drug Nexavar (sorafenib) in patients with nonsmall-cell lung cancer (NSCLC), because it was not showing the hoped for increase in survival. The ESCAPE study was a multicentre, randomized, double-blind, placebo controlled phase 3 trial involving more than 900 NSCLC patients at over 140 clinics in North and South America, Europe and Asia.
Following a planned interim analysis, the trial's independent data monitoring committee (DMC) concluded that the drug was not going to meet the trial's main goal of improving overall survival.

In conclusion, although the discontinuation of Nexavar in a phase III trial throws a shadow upon its future role in lung cancer, there are several suppooting phase II trials and it should be considered supported by medical literature.

Liu B, Barrett P, Choyke K, et al. A phase II study of BAY 43-9006 (sorafenib) in patients with relapsed non-small cell lung cancer (NCLC). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I, Vol 24, No 18S (June Supplement), 2006:abstract 17119.

Gatzemeier U, Blumenschein F, Fosella R, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I, Vol 24, No 18S (June Supplement), 2006:abstract 7002.

Gondek K, Dhanda R, Simantov R, et al. Health-related quality of life measures in advanced non-small cell lung cancer patients receiving sorafenib. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I, Vol 24, No 18S (June Supplement), 2006:abstract 17085.

Adjei AA, Mandrekar S, Marks S, et al. A phase I study of BAY 43-9006 and gefitinib in patients with refractory or recurrent non-small cell-lung cancer (NSCLC). Journal of Clinical Oncology 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005:abstract 3067.

 

Tarceva and Avastin for lung cancer

The notes suggest that the provider's first choice would have been Avastin with chemotherapy and that a combination of Avastin with Tarceva was "ordered" by the patient.

Tarceva  is FDA approved after standard chemo has failed. It is being studied for first line therapy of lung cancer instead of chemotherapy.Your stage of lung cancer is not usually treated with Tarceva and this drug has been studied primarily in stage IV, when it has spread. Studies have tended to include small numbers of IIIB patients. It is not currently FDA approved as first line therapy even for stage IV.Also in 2008, NCCN had listed Tarceva based on this evidence in this guidelines for first line therapy for EGFR+ cancer.

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.

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.

 

Abraxane for non-small cell lung cancer

Abraxane (nab-paclitaxel) is an albumin-bound, 130-nm particle form of paclitaxel that was developed to avoid cremophor/ethanol-associated toxicities associated with the parent compound. Abraxane is FDA-approved for the treatment of breast cancer after the failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Abraxane has been evaluated as a single agent in chemotherapy-naïve patients with advanced and metastatic NSCLC by Rizvi et al.[6] In this study the MTD for Abraxane administered over 30 min. on days 1, 8, and 15 on a 28 day cycle was 125 mg/m2. Premedication with dexamethasone was not required, and no hypersensitivity reactions were observed. In the extended phase II part of the study a 30% response rate and 10.9 month survival was achieved among 40 patients entered. Fatigue and sensory neuropathy were the most frequently reported toxicities resulting in discontinuation of the agent in 18 patients (45%). Nail changes and edema were other rare toxicities, and diarrhea was mild and easily manageable.

Single agent Abraxane has also been evaluated at a dose of 260 mg/m2 over 30 minutes every 3 weeks in chemotherapy-naïve patients with advanced and metastatic NSCLC.[7] Overall it was well-tolerated. Grade 3 neuropathy occurred in 2 patients after > 6 cycles. The response rate was 16% with a median TTP of 6 months and a MST of 11 mos. There are phase II studies with carboplatin.

Ongoing and future strategies with Abraxane include combinations with novel targeted agents and incorporation into the management of early-stage NSCLC. It appears that weekly Abraxane may have a better therapeutic index than an every-3-week regimen and the data in NSCLC with Abraxane has been consistent across studies. Abraxane and gemcitabine ahs been studies in breast cancer, is undergoing a phase II evaluation for pancreatic cancer but I did not find any trials for lung cancer.

Rizvi N, Azzoli C, Miller V, et al. Phase I/II study of ABI-007 as first line chemotherapy in advanced non-small cell lung cancer. J Clin Oncol 2006;24:Abstract # 7105.

Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 2006;17:1263-1268.

Hawkins MJ, Georgy M, Makhson A, et al. Dose escalation study of nab-paclitaxel followed by carboplatin as first-line therapy in advanced non-small cell lung cancer. J Clin Oncol 2006;24: 397s, Abstract # 7132.

Allerton JP, Hagenstad CT, Webb RT, et al. A phase II evaluation of the combination of paclitaxel protein-bound and carboplatin in the first-line treatment of advanced non-small cell lung cancer. J Clin Oncol 2006;24:395s, Abstract # 7127.

Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-2550.

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.

Greco A, et al. Albumin Bound Paclitaxel Wkly+Carboplatin: First-Line Therapy for Advanced NSCLC. Proceedings of the Chemotherapy Foundation Symposium XXIV. New York, New York. November 12, 2006.

Followup in lung cancer

Lay Summary: Gudelines for folowup of cancer patients are sparse. Among the few cancer types is lung. (Others include lymphoma and breast cancer).

1. In lung cancer patients who have been treated with curative-intent therapy, the follow-up for complications related to the curative-intent therapy should be managed by the appropriate specialist and should probably last 3 to 6 months. At that point, the patient should be reevaluated by the multidisciplinary tumor board for entry into an appropriate surveillance program for detecting recurrences and/or metachronous tumors. Level of evidence, poor; benefit, moderate; grade of recommendation, C
2. In lung cancer patients who have been treated with curative-intent therapy, surveillance with a medical history, physical examination, and imaging study (either chest radiograph or chest computed tomography [CT] scan) is recommended every 6 months for 2 years and then annually. Patients should be counseled on symptom recognition and should be advised to contact their physician if worrisome symptoms are recognized. Level of evidence, poor; benefit, moderate; grade of recommendation, C
3. Ideally, surveillance for the recognition of a recurrence of the original lung cancer and/or the development of a metachronous tumor should be coordinated through a multidisciplinary team approach. This team should develop a lifelong surveillance plan appropriate for the individual circumstances of each patient immediately following initial curative-intent therapy. If possible, the physician who diagnosed the primary lung cancer and initiated the curative-intent therapy should remain as the health-care provider overseeing the surveillance process. Level of evidence, poor; benefit, moderate; grade of recommendation, C
4. In lung cancer patients following curative-intent therapy, the use of blood tests, positron emission tomography (PET) scanning, sputum cytology, tumor markers, and fluorescence bronchoscopy is not currently recommended for surveillance. Level of evidence, poor; benefit, negative; grade of recommendation, D
5. Lung cancer patients who smoke should be strongly encouraged to stop smoking. Level of evidence, fair; benefit, moderate; grade of recommendation, B

Colice GL, Rubins J, Unger M. Follow-up and surveillance of the lung cancer patient following curative-intent therapy. Chest 2003 Jan;123(1 Suppl):272S-83S.

This is also the conclusion of NCCN in its followup section(except favoring non-contrast CT and mentioning that some members advocated for spiral CT) and MS-27 of the non-small cell luing guidelines. One issue that remains unclear is how long to perform annual staging.

Dose Dense TAC

Lay SUmmary: Dose dense TAC is being studied.

Since 1998, the standard of care for patients with node-positive breast cancer in the United States and other parts of the world has been treatment with doxorubicin and cyclophosphamide followed by the taxane paclitaxel. Herceptin is added for HER+ disease.  This treatment regimen was based on an intergroup study demonstrating that the addition of paclitaxel to doxorubicin and cyclophosphamide led to rates of disease-free survival of 70 percent and overall survival of 80 percent at five years, as compared with 65 percent and 77 percent, respectively, for doxorubicin and cyclophosphamide alone, with modest differences in the rate of toxic effects. This regimen was first administered on a schedule of once every three weeks and then, more recently, once every two weeks, after a comparative trial demonstrated improved efficacy (a 7 percent absolute improvement in disease-free survival and a 2 percent improvement in overall survival at three years) with the schedule involving more frequent administration (referred to as dose-dense therapy). However, dose dense TAC is only now being tested.

The approach of dose dense TAC + Herceptin warrants a discussion of several points. First, what is the status of dose dense TAC chemotherapy? Second, is the agressive approach justified?

Leaving the second question aside, the fact is that dose dense TAC is currently in a phase III cinical trial. It is now widely agreed that every three week TAC is equivalent in effectiveness of dose dense (every two week) CA = Taxol. Prelimiary results of the dose dense approach were presented in 2007 ASCO, confirming tolerabilty but without information of effectiveness. This study shows that DD TCA plus G-CSF has comparable toxicity profile with standard TCA regimen with shorter treatment period. The study is ongoing for efectiveness and the DD TAC is the research arm - investigational

S. Z. Latifzadeh, M. Salimi, M. Naghnaeian, V. Entezari Dose-dense (DD) two-weekly docetaxel/doxorubicin/cyclophosphamide (TAC) with G-CSF support compared to standard adjuvant TAC in breast cancer patients.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 11052

Marc L. Citron, Donald A. Berry, Constance Cirrincione, Clifford Hudis, Eric P. Winer, William J. Gradishar, Nancy E. Davidson, Silvana Martino, Robert Livingston, James N. Ingle, Edith A. Perez, John Carpenter, David Hurd, James F. Holland, Barbara L. Smith, Carolyn I. Sartor, Eleanor H. Leung, Jeffrey Abrams, Richard L. Schilsky, Hyman B. Muss, Larry Norton Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 Journal of Clinical Oncology, Vol 21, Issue 8 (April), 2003: 1431-1439

Edith A. Perez, M.D.  TAC — A New Standard in Adjuvant Therapy for Breast Cancer? NEJM Volume 352:2346-2348  June 2, 2005  Number 22