Recurrent Non-Small Cell Lung Cancer


When non-small cell lung cancer (NSCLC) has progressed or returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy, it is said to be recurrent or relapsed.

Patients experiencing a recurrence of NSCLC historically have had few treatment options. For those who have never been treated with chemotherapy, the approach is similar to treatment of Stage IV cancer. For patients who have already been treated with chemotherapy, new drugs—including chemotherapy and targeted therapy drugs—appear to kill more NSCLC cells.

About This NSCLC Treatment Information

The following is a general overview of treatment for recurrent NSCLC. Cancer treatment may consist of chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques—called multi-modality care—has become an important approach for prolonging survival and increasing a patient's chance of cure.

In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment.

Circumstances unique to each patient's situation influence which treatment or treatments are utilized. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Chemotherapy for Recurrent NSCLC

Chemotherapy uses drugs that kill rapidly dividing cells, a hallmark of cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs, and can be administered through a vein, injected into a body cavity, or delivered orally in the form of a pill. Chemotherapy is different from surgery or radiation therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. As a result, chemotherapy is considered a systemic treatment.

Taxotere®: Research indicates that patients treated with Taxotere survive longer than patients who receive best supportive care alone (7 months versus 4.6 months). Over one third of patients treated with Taxotere (37%) survived one year or more compared to 11% for patients who received supportive care.1

Researchers have evaluated whether adding another drug to Taxotere may improve survival, but have not found this to be the case. The addition of Camptosar® (irinotecan) to Taxotere delayed cancer progression in the treatment of patients with recurrent NSCLC compared to Taxotere alone, but the combination did not produce a significant improvement in anticancer responses or survival. 2

Alimta®: Alimta was FDA-approved for the treatment of recurrent NSCLC in 2004. When directly compared in clinical trials, Alimta and Taxotere were found to produce similar anticancer responses and duration of survival. However, patients treated with Alimta suffered from fewer severe side effects—including low levels of white blood cells, infection, diarrhea, and hair loss—and they were less likely to be hospitalized due to side effects.3

Gemzar® (gemcitabine): Combination chemotherapy that contains the drug Gemzar has been shown to offer a small advantage over other two-drug combinations in the treatment of advanced NSCLC.4

Targeted Therapy for Recurrent NSCLC

A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes.

Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing (such as blood cells and the cells lining the mouth and GI tract) are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.

Epidermal growth factor receptors (EGFRs): EGFRs are small proteins that are found on the surface of all cells. EGFRs bind exclusively with small proteins circulating in the blood called growth factors. The binding of EGFR and growth factors stimulates carefully controlled growth within the cell. However, many cancer cells—including NSCLC—have either an abundance of EGFRs or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell.

Tarceva® (erlotinib): Tarceva is a type of targeted therapy that inhibits growth of the cancer cell by binding to the inner part of the EGFR. Tarceva has been shown to improve survival and quality of life in patients with recurrent NSCLC. Patients treated with Tarceva survived two months longer than patients treated with placebo (6.7 months vs. 4.7 months). Patients who were treated with Tarceva also experienced a greater improvement in symptoms—including cough, pain, and difficulty in breathing—compared to patients who received placebo.5

Avastin® (bevacizumab): Avastin is a type of targeted therapy that slows or stops the growth of blood vessels that deliver blood to the cancer, effectively starving the cancer of the oxygen and nutrients it requires to survive and grow. Avastin, in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of unresectable (not able to be surgically removed), locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer. The combination of Avastin with paclitaxel and carboplatin has been shown to improve survival compared to chemotherapy alone.6

Managing Bone Complications in NSCLC

NSCLC cells commonly spread to the bone, causing bone metastases. Bone metastases may cause pain, bone loss, increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.

Bisphosphonate drugs can effectively prevent loss of bone that occurs from bone metastases, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone. Cancer cells release various factors that stimulate osteoclastic activity, causing increased breakdown of bone. By inhibiting osteoclasts, bisphosphonate drugs effectively reduce the detrimental impact that cancer cells have on bone density.

Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate).

Managing Anemia in Patients with NSCLC

Anemia is a condition characterized by low levels of red blood cells in the blood. Red blood cells are responsible for delivering oxygen to tissues throughout the entire body. Without enough red blood cells, the body cannot deliver enough oxygen to the body, and the resulting symptoms include fatigue, shortness of breath, greatly diminished activity levels, and a reduced overall feeling of well-being.

Cancer patients, particularly those receiving chemotherapy, often suffer from anemia. Severe anemia must be treated and may require hospitalization and blood transfusions, which have associated risks, including infection and higher medical costs. In addition, anemia can delay the administration of treatment or cause dose reductions, impeding optimal treatment benefits.

Medications such as Aranesp® (darbepoetin alfa) and Procrit® (epoetin alfa) stimulate the body to produce more red blood cells and may be used to treat chemotherapy-induced anemia in cancer patients.

Strategies to Improve Treatment of Recurrent NSCLC

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of recurrent NSCLC will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of recurrent NSCLC include the following:

Advances in Chemotherapy

Hycamtin® (topotecan): Results of a clinical trial indicate that the chemotherapy drug Hycamtin is an active treatment for patients with relapsed NSCLC and provides the benefit of oral administration. Outcomes with Hycamtin treatment appear to be comparable to outcomes from treatment with Taxotere. The number of patients who survived one year or more after treatment is similar between the two treatments: 25% for Hycamtin and 29% for Taxotere.7

Xyotax™ (paclitaxel poliglumex): Xyotax is a new form of paclitaxel that is designed to reduce side effects while maintaining the effectiveness of paclitaxel treatment. One reason that paclitaxel is difficult for many patients to tolerate is the chemical solvents—which are necessary for the drug to be administered as a liquid and effectively stored, but also cause side effects.

Results from early clinical trials have shown that Xyotax is an active treatment for recurrent NSCLC8 and shows promise as a first-line treatment for NSCLC.9

New Approaches to Targeted Therapy

A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional therapy may offer the advantage of increasing the intensity of treatment delivered to the cancer and improving outcomes without increasing treatment-related side effects. Administering targeted therapies together may also provide added benefit.

Avastin® (bevacizumab) plus Tarceva: Treatment with a combination of two targeted therapies, Avastin and Tarceva, appears to produce promising responses in the treatment of recurrent NSCLC. Avastinis type of targeted therapy that slows or prevents the growth of new blood vessels that are necessary to feed the cancer, while Tarceva directly inhibits growth of the cancer cells.

When patients with recurrent NSCLC who had received at least two prior treatments were treated with Avastin/Tarceva, 20% experienced anticancer responses and more than half (56%) had their disease stabilized. On average, the patients were free of cancer progression for 6.2 months and survived more than one year (12.6 months).10

Avastin® plus Gemzar® and Platinol®: The targeted therapy Avastin® (bevacizumab), in combination with the chemotherapy drugs paclitaxel and carboplatin, is FDA-approved for the treatment of unresectable (not able to be surgically removed), locally advanced, recurrent or metastatic non-squamous, NSCLC.

To explore the effectiveness of combining Avastin with other combination chemotherapy regimens, researchers in Germany recently conducted a phase III clinical trial to assess the addition of Avastin to chemotherapy with Gemzar® (gemcitabine) and Platinol® (cisplatin).11 The study enrolled patients with previously untreated advanced or recurrent non-squamous NSCLC. Compared to patients treated with Gemzar and Platinol alone, patients treated with Gemzar and Platinol plus Avastin had improved progression-free survival.

Zactima® (ZD6474): Zactima is a targeted therapy that inhibits the activity of two protein receptors located on the surface of cells that are involved in stimulating growth of cancer cells: EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2). Zactima appears to be a promising treatment for recurrent NSCLC when combined with Taxotere. Results of a clinical trial indicate that patients treated with Zactima plus Taxotere experienced a longer period before their cancer progressed (18 weeks) compared to patients treated with Taxotere alone (12 weeks).12 A phase III clinical trial—the research directly preceding FDA review—was started in late 2005.

Lonafarnib: Lonafarnib is a targeted therapy that is thought to disrupt growth and proliferation of cancer cells. It has produced promising results when combined with Taxol in the treatment of patients with metastatic NSCLC who had failed previous treatment with Taxol or Taxotere. Nearly half of the patients (48%) experienced a clinical benefit from treatment with lonafarnib plus Taxol. On average, patients survived 39 weeks and were free of cancer progression for 16 weeks.13

Cancer vaccines: Cancer vaccines are a type of targeted therapy that helps the body to recognize cancer cells as a threat and activates immune cells to attack the cancer.

Cancer cells are once normal cells that have gone awry. However, the immune system—the body's natural defense system against disease—does not distinguish cancer cells from normal cells. Cancer cells are permitted to grow in the body because the immune system does not recognize them as a foreign threat and so does not attack them.

Cancer cells often display certain small proteins and/or carbohydrates on their surface that are not displayed by healthy cells. Cancer vaccines often contain these proteins, and when injected into the patients, they stimulate the immune system to attack the cancer cells that display them.

Clinical study results indicate that a cancer vaccine that stimulates the body to attack cancer cells expressing the MUC1 antigen—which is often abundant on the surface of NSCLC cells—may improve survival of select patients with NSCLC.14

Iressa® (ZD 1839): Iressa is a targeted therapy that binds to a portion of the EGFR, a protein located on the surface of many cells and especially cancer cells. This binding blocks some of the actions that cause cancer cells to grow. Clinical research has revealed that only select patients respond to treatment with Iressa, which has prompted the Food and Drug Administration (FDA) to limit access to this drug, stating that it “only be used in patients who are benefiting or have benefited from Iressa. No new patients will be allowed access to Iressa unless they are being enrolled into a qualifying clinical trial.”

The patients who have been shown to benefit from treatment with Iressa are those with EGFR mutations, those of Asian ancestry, and never smokers.

More than three-quarters (82%) of patients with EGFR mutations experienced an anticancer response to Iressa compared to only 11% of patients without EGFR mutations. On average, patients with the EGFR mutation survived nearly three-times longer with Iressa treatment than patients without the mutations (20.4 months vs. 6.9 months).15

Compared to placebo, Iressa improved survival in the treatment of patients with refractory NSCLC who were of Asian ancestry (9.5 months vs. 5.5 months) or had never smoked (8.9 months vs. 6.1 months).16

Gene Therapy

Many cancer cells have genetic abnormalities that allow them to grow uncontrollably. The goal of gene therapy is to replace the inactive or dysfunctional gene with a functional gene. Researchers have discovered that one way to get the functional gene into the cell is to use a virus that causes the common cold. Since they naturally cause respiratory infections, these viruses can readily get into lung cells, where they transfer the genetic material to the cell’s DNA.

A gene therapy called Advexin® (INGN 201) is comprised of the virus and a copy of the p53 gene. Also known as the “cell-suicide gene”, p53 causes abnormal cells to die . Select patients with NSCLC have responded to treatment with Advexin.17


1 Frances A. Shepherd, Janet Dancey, Rodryg Ramlau, et al. Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy. Journal of Clinical Oncology. 2000;10:2095-2103.

2 Pectasides D, Pectasides M, Farmakis D, et al. Comparison of docetaxel and docetaxel-irinotecan combination as second-line chemotherapy in advanced non-small-cell lung cancer: a randomized phase II trial. Annals of Oncology. 2005;16(2):294-9.

3 Nasser Hanna N, Shepherd FA, Fossella FV, et al. Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy Journal of Clinical Oncology. 2004;22(9):1589–1597.

4 Schiller JH, Harrington D, Belani CP, et al. Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2002;346:92-98.

5 Shepherd F, Pereira J, Ciuleanu T, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. The New England Journal of Medicine. 2005; 353:123-132.

6 Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin Alone or with Bevacizumab for Non-small Cell Lung Cancer. New England Journal of Medicine. 2006;355:2542-50.

7 Ramlau R, Gervais M, Drzakowski M, et al. Oral topotecan demonstrates clinical activity in relapsed non-small cell lung cancer. Results from an open-label, phase III study (387) comparing oral topotecan to intravenous docetaxel. Proceedings of the 2005 meeting of the American Society of Clinical Oncology: abstract number 7017.

8 Burris H, Shipley D, Greco A, et al. Preliminary clinical and pharmacokinetic data for CT-2103 (Xyotax™) in patients with non-small cell lung cancer (NSCLC). Lung Cancer. 2003;41;Abstract P-219.

9 Nemunaitis JJ, Leighl W, Miller Y, et al. Paclitaxel poliglumex (PPX) in combination with carboplatin (carb) for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC): preliminary data. Journal of Clinical Oncology. 2005;23:667s, Abstract #7230.

10 Herbst R, Johnson D, Mininberg E, et al. Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer. Journal of Clinical Oncology. 2005;23:2544-2555.

11 Genentech. Second Phase III Study of Avastin Plus Chemotherapy Shows Improved Progression-Free Survival in First-Line Non-Squamous, Non-Small Cell Lung Cancer. Available at: Accessed September 2007.

12 Herbst R, Johnson B, Rowbottom J, et al. ZD6474 plus docetaxel in patients with previously treated NSCLC: Results of a randomized, placebo-controlled Phase II trial. Lung Cancer. 2005;49(2):S35, Abstract #o-100.

13 Kim E, Statkevich P, Munden R, et al. Phase II Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Patients with Taxane Resistant Non-Small Cell Lung Carcinoma. Cancer. 2005;104: 561-569.

14 Murray N, Butts C, Maksymiuk A, et al. BLP24 Liposome Vaccine, a MUC1 Vaccine for the Treatment of Non-Small Cell Lung Cancer. Proceedings from the 23rd annual Chemotherapy Foundation Symposium. 2005. New York. Abstract #49.

15 Takano T, Ohe Y, Sakamoto H, et al. Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer. Journal of Clinical Oncology. 2005; 23: 6829-6837.

16 Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527-37.

17 Swisher S, Roth J, Komaki R, et al. Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clinical Cancer Research. 2003;9:93-101.