Cancer Treatment

Stage IIIB lung cancer

Discussion: Chemoradiation is standard of care for stage IIIB and some IIIA non-small cell lung cancer. Stage III disease subsummizes a rather heterogeneous patient group concerning the overall prognosis including patients with more loco-regional risks (e.g. ‘T4’) or either distant risks (‘N2/N3’ or ‘large tumour burden’). Any comprehensive judgement of treatment strategies has to acknowledge this marked heterogeneity. 

Patients with proven stage III disease represent a rather heterogeneous patient population concerning co-morbidity risks including pulmonary function limitations, cardio-vascular or cerebro-vascular co-morbidities, or other major co-morbidities with evident organ dysfunctions. There may be subsets of patients that may profit from definitive surgery, but these subsets have not yet been clearly defined. There is some evidence that selected T4N0–1 patients should be taken to definitive thoracotomy. Other patients groups, including those with important co-morbidities, may have the best chance of cure and long-term survival with bi-modality protocols of concurrent chemoradiotherapy and this is the most common approach. NCCN recommends chemoradiotherapy and the recommended regimens include etoposide/cisplatin, navelbine/ cisplatin and cisplatin with gemcitabine or docetaxel. Carboplatin is sometimes used in lieu of cisplatin and there is sufficient evidence from randomized studies that complare the two, to show that these two drugs are essentially equivalent.

References:

Turrisi AT III, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265–271.[

Clamon G, Herndon J, Cooper R et al. Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 1999; 17: 4–11

A. W. Blackstock and R. Govindan
Definitive Chemoradiation for the Treatment of Locally Advanced Non Small-Cell Lung Cancer
J. Clin. Oncol., September 10, 2007; 25(26): 4146 - 4152.

A. Auperin, C. Le Pechoux, J. P. Pignon, C. Koning, B. Jeremic, G. Clamon, L. Einhorn, D. Ball, M. G. Trovo, H. J. M. Groen, et al.
Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): A meta-analysis of individual data from 1764 patients
Ann. Onc., March 1, 2006; 17(3): 473 - 483.

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.

Intrapleural chemotherapy

Intrapleural chemotherapy is given through large or small chest catheters that may be connected to an implantable port. These catheters can be used to give drugs as well as to drain fluid that often accumulates in the pleural or peritoneal cavity when cancer has spread to these areas. Malignant pleural effusion (MPE) is a common and life-threatening problem in patients with advanced malignancies. In most cases, MPE is controlled by tube drainage combined with pleurodesis and the intrapleural instillation of various sclerosing or chemotherapeutic agents. Most reports on intrapleural chemotherapy are dated and consist of case reports and case series. There are no propective studies and it is not known how it performs aganst pleurodysis or systemic chemotherapy alone.

Erasmus, Jeremy J. MD; Patz, Edward F. Jr MD Treatment of malignant pleural effusions. Current Opinion in Pulmonary Medicine. 5(4):250, July 1999.

Tan, A. Sedrakyan, J. Browne, S. Swift, and T. Treasure
The evidence on the effectiveness of management for malignant pleural effusion: a systematic review.
Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 829 - 838.

Maintenance Avastin

The trial that led to the FDA approval of avastin for nonsmall lung cancer was called ECOG 4599 (NEJM abstract here), and in that trial 878 patients with previously untreated advanced NSCLC (limited to those with nonsquamous cancers, no brain metastases, no history of coughing up blood, and not on coumadin or other blood thinners) were randomized to carbo/taxol for six cycles or the same chemo with avastin 15 mg/kg every three weeks.  For the patients who didn’t show progression of their cancer after six cycles of chemo, the protocol had patients stop the chemo and continue on “maintenance” avastin every three weeks, until they showed evidence of progression of their disease. Based on the overall survival benefit, the FDA approved avastin in this particular population, to be given with carbo/taxol, then followed by maintenance avastin.  We don’t have trial results in which avastin is given with chemo but then there’s no maintenance therapy. There was no maintenance in the breast cancer Avastin trials but one colon cancer trial did include it.

http://onctalk.com/2007/08/15/avastin-maintenance/

http://content.nejm.org/cgi/content/abstract/355/24/2542

Weekly chemotHerapy for lung cancer

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 gemcitabien/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 Avasint has been shown to add to the survival benefit. Taxotere has been established as roughly equivalent to Taxol ina 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.

Considering the variety of evidence supporting the weekly regimens' equivalence to three weekly ones, I do not expect that a phase III trial will ever test the specific regimen of weekly docetaxel/ carboplatin. I tehrefore do not conisder it experimental.

Abraxane and Avastin for lung cancer

Lay Summary: One phase II study suggests high response rates for Abraxane and Avastin in nonsmall lung cancer.

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

Tarceva with chemotherapy

Lay Summary: Tarceva is experimental together with chemotherapy but studies in specific subgroups are being conducted.

Four front-line randomized chemotherapy combination trials with gefitinib (INTACT 1 and 2) and erlotinib (TALENT and TRIBUTE) have definitely shown no benefit to adding the EGFR inhibitor to standard combination chemotherapy in patients with NSCLC. ^{I describe the best trial in some detail.}

The TRIBUTE trial was a phase III study involving patients with advanced NSCLC who had yet to be treated with chemotherapy. Most patients in the study had advanced, stage IV disease.

Between July 2001 and August 2002, researchers with the trial randomly assigned 1,079 patients to one of two groups. One group (539) was treated with a standard chemotherapy regimen of paclitaxel (Taxol®) and carboplatin, plus a daily erlotinib pill. The other group (540) received the same chemotherapy treatment plus a dummy pill (placebo).

The trial was primarily designed to determine whether patients taking the erlotinib combination did better in terms of overall survival. However, based on encouraging results from earlier studies, the researchers also designed the trial to see if a particular subgroup of patients – those who had never smoked – did better on erlotinib.

A related analysis was done on tumor samples provided by 274 of the 1,079 patients. Drawing on the results of previous tissue sample studies, researchers looked for the presence of certain EGFR mutations in this group of NSCLC patients and whether they were associated with better or worse survival and other outcomes.

The clinical trial team was led by Roy S. Herbst, M.D., Ph.D., of the University of Texas M.D. Anderson Cancer Center in Houston (see the journal abstract). The tissue study team was led by David A. Eberhard, M.D., Ph.D. of Genentech, Inc. in San Francisco, Calif. (see the journal abstract). Both reports were published in the same journal issue.

Results

Erlotinib did not help patients live any longer overall. The median survival for patients taking erlotinib was 10.6 months compared to 10.5 months for the placebo group. Both groups of patients also experienced about the same “time to progression” (the time it took for their cancer to get worse): 5.1 months for the erlotinib group, 4.9 months for the placebo group.

Erlotinib failed to make any difference among most of the subgroups analyzed, including those defined by age, gender, race, and the level of EGFR expression. However, erlotinib did help the subgroup which had never smoked. The 72 “never smokers” in the erlotinib group survived 22.5 months; the 44 never smokers in the placebo group lived 10.1 months. This amounted to a 51 percent reduction in the risk of dying for the erlotinib group.

Never smokers on the erlotinib combination also did better in terms of time to progression (6.0 months) when compared to never smokers in the standard chemotherapy group (4.3 months) – a 50 percent reduction in risk of progression.

As for side effects, all patients in both groups experienced about the same level of toxicity, though those taking the erlotinib combination experienced more instances of rash and diarrhea. These particular side effects are known to be associated with EGFR inhibitors such as erlotinib.

In the related tissue sample analysis, researchers reported that certain EGFR mutations were found in 13 percent of the samples provided. (The rest of the tumors expressed what researchers call the “wild type” form of EGFR.) Patients with EGFR mutations tended to live longer, regardless of whether they were taking the erlotinib combination or just the standard chemotherapy. Among the never smokers, those in the erlotinib group tended to have more of these mutations than those in the chemotherapy-only group.

A number of other patterns were noted about patients with EGFR mutations, leading the researchers to suggest that the mutations may help doctors determine which advanced NSCLC patients are most likely to benefit from treatment with or without erlotinib. Studies that stratify patients based on their EGFR status are ongoing.

nccn.org, nonsmall cell lung cancer

S Tort, D Gallardo, FR Macbeth, MC Pallarès, I Solà Erlotinib for advanced non-small cell lung cancer Cochrane Database of Systematic Reviews 2008 Issue 1

revised: 2/13/08

Erbitux for lung cancer

Lay Summary: Erbitux is proving to be an active and importatn agent for lung cancer.

Erbitux binds specifically to epidermal growth factor receptors on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor and other ligands. It is approved for use in combination with irinotecan to treat patients with EGFR-expressing metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and as a single agent in the patients intolerant to irinotecan-based chemotherapy.

A Phase III study of ERBITUX® (Cetuximab) in combination with platinum-based chemotherapy (vinorelbine plus cisplatin) met its primary endpoint of increasing overall survival compared with chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC). This large, randomized multi-national study, known as FLEX (First-Line Treatment for Patients with Epidermal growth factor inhibitor (EGFR)-EXpressing Advanced NSCLC) was conducted by Merck KGaA, Darmstadt, Germany and enrolled patients with Stage IIIB or Stage IV NSCLC who had not previously received chemotherapy.  The results were announced in September on 2007 and published in December.

These results are not yet reflected in guidelines or most policies. However, they need to be considered as grounds for approval.

Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, Kreisman H, Graze P, Maher J, Ross HJ, Ellis PM, McNulty W, Kaplan E, Pautret V, Weber MR, Shepherd FA.

Neoadjuvant chemo for lung cancer

Lay Summary: Chemotherapy has at least three distinct roles in various non-small lung cancer situations.

Neoadjuvant therapy for locally advanced non-small cell lung cancer has evolved rapidly near the turn of the century. Historically, radiation used to be the only treatment for unresectable non-small cell lung cancer. In 1990, Dillman et al introduced the use of neoadjuvant cisplatin-based chemotherapy before radiation with better survival, and other chemotherapy regimens used in this fashion also yielded comparable results. Nevertheless, adding adjuvant chemotherapy after radiation provided no additional benefit. Subsequently, the use of neoadjuvant chemotherapy followed by radiation waned, when concurrent chemoradiation had been found to produce better survival outcome. Today, concurrent chemoradiation is the standard of care for patients with unresectable non-small cell lung cancer who have good performance status.

In certain situations, concurrent chemoradiation has transformed its role from a definitive treatment into a neoadjuvant treatment before radical resection. Concurrent chemoradiation may render some unresectable non-small cell lung cancers resectable. Although no data from randomized, controlled trials are available, it is evident that patients with superior sulcus tumor or pancoast tumor, after undergoing neoadjuvant radiation with or without concurrent chemotherapy, may become eligible for complete resection and achieve prolonged disease-free survival.

For patients with resectable but locally advanced non-small cell lung cancer, outcome of treatment with surgery alone is poor. Several small, randomized studies suggest that neoadjuvant chemotherapy before surgery improves overall survival when compared with surgery alone. One such study, for instance, using 3 cycles of chemotherapy followed by surgery, demonstrated an increase in median survival from 8 months in the surgery-alone arm to 26 months in the neoadjuvant arm. Subsequent larger studies, however, produced conflicting results. Other investigators have experimented with concurrent chemoradiation followed by surgery in comparison with chemoradiation alone.[48] Preliminary data indicate that patients who respond well to chemoradiation may benefit from subsequent surgery, although long-term follow-up is still necessary.

1. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692-2699.
2. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001;121:472-483.

nccn.org, lung cancer

Alimta and cisplatin or carboplatin for NSCL

Lay Summary: Alimta and cisplatin are FDA approved for second line therapy of lung cancer. It is an effective regimen in first line as well. Carboplatin can be substituted for cisplatin.

The National Comprehensive Cancer Network (NCCN), an alliance of nineteen of the world’s leading cancer centers, recently added pemetrexed (Alimta®, Eli Lilly and Company) as an option for second-line therapy for lung cancer. The panel indicated that it has been shown to be equivalent to docetaxel (Taxotere®, Sanofi-Aventis) in efficacy but with less toxicity.  The U.S. Food and Drug Administration granted accelerated approval for Alimta for the treatment of locally advanced or metastatic non-small cell lung cancer in previously treated patients in 2004. It is FDA approved for mesothelioma in combination with cisplatin.

ALIMTA® (pemetrexed for injection) showed additional utility in the treatment of the most diagnosed type of cancer , according to data presented at the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO). Results from a Phase III study suggest that a first-line ALIMTA-based regimen may deliver less toxicity than a commonly used therapy in advanced non-small cell lung cancer (NSCLC). ALIMTA is manufactured and marketed by Eli Lilly and Company.

A prospective, randomized, multicenter Phase III study was conducted to compare ALIMTA plus carboplatin with the commonly used regimen of GEMZAR® (gemcitabine HC1 for injection) plus carboplatin (ASCO Abstract # 7517 ). The study, conducted by the Norwegian Lung Cancer Group, enrolled 446 chemonaïve patients with either stage IIIB or IV NSCLC. The primary purpose of the study was to evaluate if the ALIMTA-carboplatin combination provided increased quality-of-life benefits while offering comparable survival data. As such, the primary endpoint was quality of life (defined in the study as nausea/vomiting; dyspnea or a difficulty in breathing, and; fatigue) and the secondary endpoint was overall survival.

Thus far, 384 patients have been analyzed for toxicity and there were fewer patients in the ALIMTA arm who experienced Grade 3/4 thrombocytopenia or a low platelet level (48 vs. 107, p<.001); leukopenia or a lowering of leukocyte white blood cells (44 vs. 89, p<.001), and; granulocytopenia or a lowering of granulocyte white blood cells (78 vs. 98, p=.02). More patients in the GEMZAR arm received transfusion of platelets (5 vs. 19, p=.02). At this point, no difference in survival has been observed.

Eli Lilly and Company has submitted an application with the European Medicines Agency (EMEA) for centralised review of ALIMTA (pemetrexed for injection), in combination with cisplatin, for the first-line treatment of advanced non-small cell lung cancer (NSCLC).
The EMEA submission is based on a study which evaluated ALIMTA plus cisplatin versus GEMZAR (gemcitabine HCl for injection) plus cisplatin. The study met its primary endpoint of non-inferiority relative to overall survival in a first-line NSCLC setting. These studies have been presented at ASCO in 2007.

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.

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.

nccn.org