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Drug therapy for non-small cell lung cancer


Medical editor Odd Terje Brustugun MD
Oncologist

Oslo University Hospital
Norway

General

Chemotherapy for non-small cell lung cancer is used as adjuvant treatment after curative surgery and in combination with radical radiation therapy. It will also often be relevant in palliative situations.

Adjuvant chemotherapy

Adjuvant chemotherapy has been shown to increase survival after surgery for patients with stage II and stage III cancer, but this effect is not seen for patients in stage IA. Benefit may be seen in stage IB cancers more than 4 cms in maximal dimension. Five year survival increases by 5-15% in absolute figures. Chemotherapy can be given in combination with curative radiation therapy (concomitantly). Neoadjuvant chemotherapy is usually not given for non-small cell lung cancer, except in some cases of Pancoast syndrome (apical lung tumors invading the thoracic wall).

Palliative chemotherapy

At the time of diagnosis, 70% of patients with non-small lung cancer are in a palliative stage. In patients of this group, platinum-based chemotherapy may relieve symptoms or delay the appearance of such, and thereby improve quality of life. Furthermore, palliative chemotherapy prolongs survival for some months. A prerequisite is that the patient is in good general health, i.e. performance status (PS) 0-2. Response to palliative conventional chemotherapy is expected in about 3 of 10 patients in first-line situations and in 1 of 10 by second-line treatment. At present it is not possible to predict whether a patient will benefit from chemotherapy.

Patients with activating mutations in the gene that codes for epidermal growth factor receptor (EGFR), about 10% of all, should be offered peroral treatment with tyrosin kinase inhibitors, such as erlotinib, gefitinibor or afatinib. Such therapy has shown significantly better efficacy than conventional chemotherapy. The response rate are approximately 70% in patients positive for this mutation. Time to disease progression is on average about one year.

About 5% of the patients with non-small cell lung cancer have changes in the ALK gene.
The ALK inhibitors have shown effectiveness in these patients similar to patients treated with EGFR inhibitors mentioned above. Crizotinib is an oral ALK inhibitor and approved as second line treatment in ALK-positive patients.

EGFR-mutation status should also be analyzed in conjunction with histopathological diagnostics whenever a NSCLC of non-squamous cell carcinoma subtype.

Predictive factors

The most important predictive factor for chemotherapy effect, except for the TNM stage, is performance status. The risk of serious side effects increases in patients with a performance status of 3 or 4. In these cases, chemotherapy is not recommended. Norwegian data indicates that performance status 2 has the greatest benefit from treatment in terms of improved quality of life, since symptom relief exceeds side effects to a greater degree than in those with better general health condition. Tyrosin protein kinase inhibitors have a different side effect-profile than conventional chemotherapeutics, and can be tried out in mutation-positive patients with performance status 3.

Chemotherapy in elderly patients with non-small cell lung cancer

Over half of patients with non-small cell lung cancer are older than 65. However, elderly patients are underrepresented in clinical studies and the evidence for chemotherapy in this group is therefore limited. Functional level, comorbidity with polypharmacy, socioeconomic and cognitive factors, as well as nutritional status, can vary significantly among this heterogeneous patient group. The decision to administer chemotherapy should be based on a total geriatric assessment of these factors. Patients in good general health status (PS 0-2) with normal organ function may benefit from platinum-based doublet chemotherapy. Elderly patients of a reduced general health condition are offered monotherapy with a newer drug such as vinorelbine, gemcitabine, pemetrexed (only non-squamous carcinoma), docetaxel or, in mutation-positive patients, tyrosine kinase inhibitors.

Indications

  • Postoperative chemotherapy – patients in stage II and III who have been operated. 
  • Chemotherapy in combination with curative radiation treatment - patients in stages IIIa and IIIb who can receive curative radiation treatment.
  • Palliative chemotherapy – patients with stage IV.

Goal

  • For postoperative chemotherapy and chemotherapy given in combination with curative radiation therapy, the goal is to increase the probability of curing the disease.  
  • Relieve symptoms and ailment, and prolong life, in palliative treatment.

Treatment Plan

The treatment plan for patients with non-small cell lung cancer is available via the interactive flow chart. This is a function which provides overview of treatments for the patient groups.

Click to open the flow chart

Choice of medication

The available documentation for adjuvant chemotherapy applies to a platinum-based doublet. Cisplatin combined with vinorelbine is recommended for 4 cycles. 

For non-mutated metastatic cancer, there is convincing documentation that first-line treatment should be platinum-based chemotherapy (either cisplatin or carboplatin) combined with a newer drug such as vinorelbine, gemcitabine, docetaxel, paclitaxel or pemetrexed. None of the regimens seems superior, but in Norway the combination carboplatin and vinorelbin is used most frequently. Non-platinum-based regimens should not be used outside of studies in first-line treatment. Gefitinib, erlotinib or afatinib is used in first-line treatment in EGFR-mutation positive patients. Patients should be asked whether they would like to participate in a clinical study prior to starting treatment. There is documentation that patients participating in studies benefit in terms of survival.

Recurrence/second-line treatment

Patients to be treated for recurrence will often be asked to participate in studies.

If the patient has previously only received radiation, the first choice treatment is a platinum-based doublet or inclusion in studies as mentioned above.

Possible treatments in second-line include monotherapy with docetaxel or pemetrexed (in non-squamous cell carcinomas). Unfortunately, the response rates for second-line conventional chemotherapy are low, at about 10%. If previously responsive or after three months from concluded first-line treatment, the same drug combination could be repeated.

Afatinib, erlotinib or gefitinib is treatment of choice in EGFR-positive patients, if EGFR-inhibitor was not used in the first-line treatment. Crizotinib should be offered to ALK-positive patients. These peroral inhibitors, may also be suitable as a third-line medication with performance status up to PS 3, if not given previously. Otherwise, for PS 3-4, good supportive care without tumor-directed treatment is often the optimal treatment.


Preparation

The patient is thoroughly oriented, verbally and in writing, about the goal of the treatment, how it will be carried out, what side effects can be expected, and what is expected from the patient during the treatment period. 

For treatment of lung cancer with chemotherapy, neutropenia is the most common cause of dose reduction. Blood tests must therefore always be performed before starting a new course of treatment. 

For cisplatin-containing chemotherapy regimens, kidney function must also be monitored. 

The patient will be offered a customized wig.


Implementation

Adjuvant chemotherapy

  • Postoperatively, 4 courses of cisplatin and vinorelbine are administered intravenously.  
  • For chemotherapy in combination with radiation therapy for stage III, two courses of cisplatin and etoposide (PV) are usually given concominantly with radiation.  
  • Preoperatively in Pancoast syndrome 2 courses of a cisplatin-based combination at three week intervals, combined with radiation therapy, 2 Gy x 25 can be administered.

Palliative chemotherapy

Three-four courses with three week intervals are given. Carboplatin/vinorelbine is administered with carboplatin day 1, and vinorelbine day 1 and 8, with new treatment course starting on day 22.  


Follow-up

The treatment effect is most often evaluated at 2-3 month intervals. The first follow-up should take place 4-8 weeks after treatment is concluded.

Evaluation often includes pulmonary X-ray or CT.

 

Some side effects of chemotherapy for non-small cell lung cancer (1)

(Frequent> 1/100, rare < 1/1000)

Side Effect      Cisplatin Carboplatin Vinorelbine Docetaxel  Gemcitabine  Premed-
trexed
Erlotinib
Bone marrow depression Frequent Frequent Frequent Frequent Frequent Frequent Not reported
Nausea/Vomiting Highly
emetic
Moderately
emetic

Mildly
emetic

Mildly
emetic
Mildly
emetic

Mildly emetic

Moderately
emetic
Hair loss Rare Frequent Frequent Frequent Frequent Frequent Frequent
Diarrhea/
Constipation
Diarrhea/
frequent
Frequent

Frequent

Frequent Frequent Rare Diarrrhea/
frequent
Mucositis/
Stomatitis
Not reported Not reported

Stomatitis/
frequent

Stomatitis Stomatitis Frequent

Stomatitis/
frequent

Allergic reactions Rare Frequent Rare Frequent Rare Rare Not reported

Cardiotoxicity

Rare Frequent Not reported Frequent Rare Rare Not reported
Neurological symptoms Frequent Frequent Frequent Frequent Rare Rare Not reported
Skin/nails Rare Frequent Rare Frequent Frequent Frequent Frequent
Liver Frequent Frequent Frequent/
mild
Frequent Frequent Rare Frequent
Airways Not reported Not reported Not reported Rare Frequent Not reported Rare

Ototoxic side effects are experienced in about 30% of patients receiving cisplatin.

 

Reference

  1. Felleskatalogen [online] [retrieved 14.09.2007]; Available at: URL: http://www.felleskatalogen.no

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