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Postoperative adjuvant chemotherapy in NSCLC


Johan Vansteenkiste
Respiratory Oncology Unit and Leuven Lung Cancer Group
University Hospital Gasthuisberg
E:[email protected]

The TNM stage, in addition to performance status (an index of the general fitness of the patient), is the most important tool to help estimate prognosis in lung cancer patients and choose the best combination of treatment modalities, such as surgery, radiation or chemotherapy. In the TNM staging system, the T factor describes the primary tumour, the N factor describes the loco-regional lymph node spread and the M factor points at the absence or presence of distant metastases.

Conventional staging relies on clinical examination, imaging tests, such as computed tomography (CT) scan, and invasive techniques, such as bronchoscopy or mediastinoscopy. In the past 5–10 years, the use of positron emission tomography (PET) with the tracer (18)F-2-fluoro-2- deoxyglucose (FDG) has been an important improvement in lung cancer staging. This technique is based on the higher glucose consumption in tumour tissue, which is visible with the PET camera after injection of the radiolabelled glucose analogue FDG. Staging with FDG-PET is significantly more accurate than conventional staging, and addition of this technique to conventional imaging has resulted in better patient management (eg, reduction of unnecessary lung cancer surgery).(1) The use of FDG-PET is currently being further explored in the assessment of prognosis and response to therapy.(2)

Therapy largely depends on the stage of the disease. Patients are grouped in stages with similar prognosis according to their T, N and M classification. For practical clinical considerations, patients with stage I and II are often referred to as “early stage”. Stage III patients have “locally advanced disease”, and stage IV patients have “advanced” or “metastatic” disease.

Improvements in early-stage NSCLC
The conventional approach to early-stage nonsmall-cell lung cancer (NSCLC) is local treatment, preferably surgical resection, or radical radiotherapy in case of poor cardiopulmonary function. After resection of early-stage lung cancer, about 40% of the patients are cured; these results have been unchanged for the past 20 years.

It has recently been discovered that adjuvant chemotherapy can be used in the treatment of lung cancer. The Adjuvant Lung cancer Trial (IALT), one of the largest studies ever carried out in NSCLC, randomly assigned 1,867 operated patients to either postoperative cisplatin (Platinol)-based chemo-therapy or follow-up only.(3) Postoperative chemo-therapy resulted in a 14% reduction in mortality and a significantly improved five-year survival rate (44.5% in the chemotherapy arm, versus 40.4% in the control arm; p<0.03). The positive effects of adjuvant chemotherapy were confirmed in two smaller North American studies.

Overall, these results confirm that, in many patients, even early-stage NSCLC is a systemic disease, with better treatment outcome if systemic therapy (chemotherapy) is added to local therapy (surgery). The next step will be to examine whether preoperatively administered (neoadjuvant) chemo-therapy gives better results (which should theoretically be the case). In addition, neoadjuvant chemotherapy is usually better tolerated. An encouraging result has already been reported,(4) and several phase III randomised studies are currently addressing this important issue.

Improvements in locally advanced NSCLC
Patients classified as stage III should be divided into stage IIIA (N2: lymph node spread in the ipsilateral mediastinal nodes only) or IIIB (N3: lymph node spread in the contralateral mediastinal or supra-clavicular nodes).

The approach for stage III patients was traditionally radiotherapy alone, or in some cases surgery alone, with marginal five-year survival rates. Recent data show that better prospects for remission, and sometimes cure, can be obtained if patients are treated with a combination of local and systemic treatments.

For European stage IIIA patients, induction chemotherapy followed by attempted complete resection is usually carried out, whereas chemoradio-therapy approaches are more common in North America, with the surgery component still under discussion. In our experience, the use of cisplatin-based preoperative chemotherapy results in a clear improvement for these patients. In the historical “surgery alone” group (based on a restrictive attitude with surgery only for patients with minimal lymph node metastases), the median survival times and five-year survival rates were 12 months and 15%, respectively. In a recent cohort study,(5) all patients with lymph node metastases, even bulky ones, were treated with chemotherapy followed by attempted surgical resection. The median survival times and five-year survival rates of the total group were 24 months and 21%, respectively (45 months and 35% for the surgically-treated group, respectively). Further randomised studies are needed to confirm these encouraging findings.

Stage IIIB patients are no longer amenable to surgery, and, in this case, combination of chemo-therapy and radiotherapy is superior to radiotherapy alone. Debate is ongoing on whether the components should be given sequentially (chemotherapy followed by radiotherapy) or concurrently.

Improvements in advanced NSCLC
Patients with advanced NSCLC are no longer amenable to cure, and the aim of treatment is to improve survival rates, with good quality of life (QoL).

Data suggest that there is a plateau in the survival rates that can be obtained with the type of chemotherapy currently used.(6) Chemotherapy is generally based on a platinum compound (cisplatin or carboplatin ) and a third-generation cytotoxic drug such as gemcitabine (Gemzar), docetaxel (Taxotere), paclitaxel (Taxol), pemetrexed (Alimta) or vinorelbine (Navelbine). Modern combination chemotherapy is better tolerated than previous chemotherapies. Third-generation drugs are even active as single-agent therapy. In both instances, this results in better QoL outcomes for the patients.

Furthermore, improvements have also been made in supportive care. Darbepoetin alfa (Aranesp) is an effective and long-acting erythropoietic agent in the treatment of chemotherapy-related anaemia, which often has a major impact on fatigue and QoL.(7) Whereas the label of epoetin alfa recommends three subcutaneous injections per week, darbepoetin alfa can be administered once every three weeks, which is more convenient for the patient. Long-term-acting growth factors such as pegfilgrastim (Neulasta) have also dramatically reduced the number of injections needed for the treatment of chemotherapy- induced neutropenia. Setrons (5-HT(3) receptor antagonists) such as ondansetron (Zofran) or tropisetron (Novaban) largely improve nausea and emesis associated with chemotherapy; the next generation of antiemetics, the neurokinin antagonists (which are currently undergoing large-scale clinical testing), are expected to be a further improvement in this field.

Finally, the increasing understanding of the molecular biology of lung cancer has led to the development of targeted agents. These agents usually target a specific receptor or protein that is essential for tumour growth and proliferation. Gefitinib (Iressa), an orally active epidermal growth factor receptor tyrosine kinase inhibitor that is currently at the advanced stages of clinical development, is the first agent of its kind to have received approval in a large number of countries. Large-scale randomised trials showed that gefitinib administered in heavily pretreated patients with advanced NSCLC (who are usually thought to have no further treatment options) resulted in durable disease stabilisation and symptom control in 40% of these patients.(8)

Practical implications at the hospital pharmacy level
It is expected that the prescription of chemotherapy will increase, mainly because postoperative adjuvant chemotherapy is becoming the new standard of care. Another factor is the increasing number of active cytotoxics, which allows rewarding second-line treatment. Finally, single-agent therapy with a third-generation drug such as gemcitabine or docetaxel is generally well tolerated, so that even patients with poor general condition can benefit from treatment.

As new haematopoietic growth factors such as darbepoetin alfa and pegfilgrastim can be administered every three weeks, an increased use of these agents is also to be expected.

Finally, molecular–biological agents such as gefitinib have reached the late stages of development and registration in many countries. Other similar agents should soon follow. This important new element in the fight against lung cancer should mainly affect ambulatory prescription patterns.


  1. Van Tinteren H, Hoekstra OS, Smit EF, Van Den Bergh JH, Schreurs AJ, Stallaert RA, et al. Lancet 2002; 359:1388-93.
  2. Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Lancet Oncol In press 2004.
  3. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. N Engl J Med 2004;350:351-60.
  4. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. J Clin Oncol 2002;20:247-53.
  5. Lorent N, Vansteenkiste J, De Leyn P, Lievens Y, Verbeken E, Nackaerts K, et al. Ann Oncol In press 2004.
  6. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. N Engl J Med 2002;346:92-8.
  7. Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, et al. J Natl Cancer Inst 2002;94:1211-20.
  8. Fukuoka M, Yano S, Giaccone G, Tamura T, Douillard JY, Nishiwaki Y, et al.  J Clin Oncol 2003;21:2237-46.

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