1

Describe the cell cycle (Figure 1)

The cell cycle is a process of cell division and replication.

In eukaryotic cells, the cycle is divided into three phases:

a)

interphase, which is subdivided into:

i)

growth phase (G1);

ii)

DNA replication phase (S);

iii)

period of further cell growth (G2);

b)

mitotic phase of cell division (M);

c)

quiescent phase (G0), prior to the commencement of a further cycle.

2

What are the indications for chemotherapy?

Stand-alone treatment:

a)

radical chemotherapy – which may be given with curative intent, such as for lymphoma and germ cell tumours;

b)

palliative chemotherapy – where the treatment is given for symptom relief in patients where a cure is not possible.

Combination therapy with surgery and/or radiotherapy:

a)

induction therapy – treatment given with the aim of downstaging a tumour from an inoperable to an operable stage;

b)

neoadjuvant therapy – pre-operative treatment aimed at improving the survival rate in an operable tumour;

c)

adjuvant therapy – postoperative treatment aimed at improving the cure rate in an operable tumour.

3

What are the mechanisms of action of the chemotherapeutic agents used in the management of thoracic oncology?

Drugs targeting activity in the nucleus:

a)

cisplatin and carboplatin are both platinum-based drugs, which alkylate DNA, causing inter- and intra-strand cross-linking that interferes with DNA repair;

b)

etoposide is a topoisomerase II inhibitor, which causes DNA double-strand breaks resulting in apoptosis;

c)

gemcitabine is a nucleoside analogue, which inhibits ribonucleotide reductase and when phosphorylated is incorporated into DNA resulting in apoptosis.

Drugs interfering with cellular function:

a)

paclitaxel and docetaxel are taxanes, which interfere with the function of microtubules during mitosis;

b)

vinorelbine is a vinca alkaloid, which has anti-mitotic properties by destroying mitotic spindles;

c)

pemetrexed is a folate antimetabolite, which inhibits purine and pyrimidine synthesis by inhibition of thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT).

Growth and migration inhibitors:

a)

erlotinib, gefitinib and afatinib are tyrosine kinase epidermal growth factor receptor (EGFR) inhibitors, which halt cell proliferation;

b)

crizotinib is an ALK (anaplastic lymphoma kinase) tyrosine kinase inhibitor, which modulates growth, migration and invasiveness of malignant cells.

Monoclonal antibodies:

a)

bevacizumab is a monoclonal antibody, which binds vascular endothelial growth factor A (VEGF-A), preventing its interaction with VEGF receptors and thereby inhibiting angiogenesis;

b)

cetuximab is a monoclonal antibody against the EGFR extracellular domain, with downstream effects on cell proliferation via inhibition of signalling.

4

What are first-line and second-line therapies?

First-line therapy (induction therapy or primary therapy) is the first treatment given for any pathology, as recommended by the best evidence available. It is often part of a standard protocol, such as surgery followed by chemotherapy and radiation.

Second-line therapy involves the use of additional or alternative agents after the completion of first-line therapy when:

a)

the disease is not controlled or recurs;

b)

unacceptable side effects occur.

5

What is maintenance chemotherapy?

Maintenance chemotherapy is the use of systemic therapy immediately or soon after first-line chemotherapy in the absence of disease progression.

There are two types of maintenance chemotherapy:

a)

continuation maintenance, when one or two of the first-line drugs are continued, such as continued pemetrexed therapy following pemetrexed and cisplatin chemotherapy;

b)

switch maintenance, where different drugs are used, such as maintenance pemetrexed following first-line gemcitabine and cisplatin chemotherapy.

Maintenance chemotherapy is used after first-line treatment for advanced NSCLC when there is tumour response or stable disease providing the patient is tolerating therapy.

6

How is the response to chemotherapy assessed?

Response Evaluation Criteria in Solid Tumours (RECIST) is utilised to assess tumour response to treatment.

This includes a combined assessment of all existing lesions, characterised by target lesions (a maximum of five lesions per organ and ten lesions in total) to be measured, and non-target lesions that are only noted.

A sum of the longest diameter for all target lesions is calculated and reported as the baseline sum longest diameter.

Responses are defined as:

a)

complete response (CR) – disappearance of all defined target lesions. The CR rate of NSCLC to chemotherapy is 5%;

b)

partial response (PR) – which represents at least a 30% decrease in the sum of the longest diameter of target lesions. The PR rate of NSCLC to chemotherapy is 40-50%;

c)

stable disease (SD) – neither sufficient shrinkage to qualify for regressive disease nor sufficient increase to qualify for progressive disease. The SD rate of NSCLC to chemotherapy is 30%;

d)

progressive disease (PD) – at least a 20% increase in the sum of the longest diameter of target lesions. The PD rate of NSCLC to chemotherapy is 20%.

7

What is targeted therapy?

Targeted therapy represents the use of agents designed to inhibit or affect genetic mutations or over-expression of proteins within the tumour or molecules required by the tumour cell for growth with minimal effects against normal cells.

Agents used as targeted therapy include monoclonal antibodies, small-molecular-weight inhibitors or oligonucleotides targeting RNA or DNA, including:

a)

bevacizumab and cetuximab, which target VEGF and EGFR proteins, respectively;

b)

erlotinib and gefitinib, which target the intracellular domain of the EGFR receptor protein;

c)

crizotinib, which is an ALK (anaplastic lymphoma kinase) inhibitor;

d)

cetuximab, which is an EGFR inhibitor.

8

What are the side effects of chemotherapy in general?

Alopecia.

Gastrointestinal side effects – nausea, vomiting, diarrhoea.

Myelosuppression – immunosuppression, anaemia, thrombocytopaenia.

Mucositis.

Lethargy.

Organ-specific side effects – cardiotoxicity, hepatotoxicity, ototoxicity, neuropathy, infertility and teratogenicity.

Tissue inflammation and necrosis if extravasated.

New malignancy.

9

What are the side effects of the specific chemotherapeutic agents used in the management of thoracic oncology (Table 1)?

In addition to myelosuppression and upper gastrointestinal upset, the drugs outlined in Table 1 are particularly associated with the listed side effects which occur in more than 50% of patients.

10

What are the indications for cessation of first-line chemotherapy?

Disease progression.

Unacceptable toxicity.

Worsening WHO performance status to 3 or 4.

Non-response after four cycles.

Six cycles are usually the maximum number of cycles of chemotherapy in patients who demonstrate a response to therapy in the first- or second-line setting.

Patient choice.

11

What are the indications for chemotherapy in lung cancer (Figure 2)?

Adjuvant treatment following complete resection of early-stage non-small cell lung cancer (NSCLC).

Induction treatment or definitive treatment of inoperable Stage IV NSCLC, either alone or in combination with radiotherapy.

First-line treatment for locally advanced Stage IIIB, either alone or in combination with radiotherapy.

First-, second- and third-line treatment of Stage IV.

First- and second-line treatment of small cell lung cancer (SCLC).

12

What are the indications for adjuvant chemotherapy in completely resected NSCLC?

T1-3, N1-2, M0.

Tumours ≥4cm.

A 4.8% improvement in 5-year survival.

Postoperative chemotherapy may also be considered where pathologic staging has shown unexpected advanced disease, such as N3, T4, and M1a disease, but is not categorised as adjuvant treatment in this context.

13

What adjuvant chemotherapeutic regime is recommended following complete resection of NSCLC?

Cisplatin plus vinorelbine.

Subgroup analysis of the LACE-vinorelbine cohort showed superior overall survival (8.9% at 5 years) and disease-free survival compared to those patients receiving cisplatin with other agents, although the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.

14

What are the stage-specific benefits of adjuvant chemotherapy in patients with completely resected NSCLC?

The stage-specific 5-year survival benefits for adjuvant chemotherapy versus surgery alone are:

a)

Stage IB – 67% vs. 64%;

b)

Stage II – 49% vs. 39%;

c)

Stage IIIA – 39% vs. 26%.

15

What are the effects of the 7th edition of the AJCC/UICC TNM classification when considering adjuvant chemotherapy for patients with completely resected NSCLC?

Based on current indications for adjuvant treatment, it is estimated that up to one-fifth of patients could be offered different treatment: