Lung Cancer Systemic Treatment Guidelines

Lung Cancer Systemic Treatment Guidelines

1. Adjuvant Therapy for NSCLC

1.1 Background

1.2 Treatment Regimen for Adjuvant Therapy for NSCLC

2 Locally Advanced NSCLC

2.1 Background......

2.2 Staging

3 Advanced (Metastatic and Stage IIIB wet) NSCLC

3.1 Background

3.2 Treatment Regimens for advanced NSCLC

4. Chemotherapy Guidelines for SCLC

4.1 Background

4.2 Staging

4.3 First Line Treatment of SCLC

4.4 Second Line Treatment of SCLC

5. Treatment Guidelines for Malignant Pleural Mesothelioma

5.1 Background

5.2 Treatment Regimen for Malignant Pleural Mesothelioma

6. Supportive Therapies

7. References

1. Adjuvant Therapy for NSCLC

1.1 Background

Adjuvant chemotherapy for NSCLC is based on the premise that recurrence following resection of primary disease can be systemic as well as local. The majority of patients who survive surgery should be fit enough to be considered for adjuvant chemotherapy.

Evidence supporting the use of platinum based adjuvant chemotherapy comes from several large randomised controlled studies and two meta-analyses[1]. Together these studies provide evidence of a survival benefit which is at least as good as that seen for adjuvant chemotherapy in other settings such as breast or colorectal cancer.

In February 2005 NICE issued guidance on adjuvant chemotherapy for NSCLC: the conclusion was that chemotherapy offered small but significant benefit for patients following surgery and patients should be considered for platinum based treatment.

No comment was made on which regimen should be used, however it seems reasonable to assume that treatment with platinum plus one of the 3rd generation agents (vinorelbine, gemcitabine, docetaxelorpaclitaxel) would be more effective than the older MIC or MVP type regimen (as has been shown for advanced disease).

1.2Treatment Regimen for Adjuvant Therapy for NSCLC

1.2.1 Patient selection

Consider Adjuvant Therapy for Post-operative patients with:

•Stage IB (4cm or more) to III disease

•Good performance status (ECOG0-1)

•Adequate renal (Cr Cl >50), liver and bone marrow function

•Staging carried out pre-op with CT Scan and PET scan is adequate

•Brain scan not required unless symptomatic

1.2.2 Treatment Regimen

Cisplatin 75mg/m2 day 1 and Vinorelbine 25mg/m2 day 1 & 8[1]

4 cycles

Prophylactic ciprofloxacin 500mg bd with cycle 1 day 5-14

1.2.3 Follow up

Initially 1 month after treatment finishes

3 monthly until 2 years from surgery

6 monthly years 3-5

annually years 5-10 (for collection of follow-up data).

No repeat scan unless symptoms indicate need.

For CXR at every other visit or as clinically indicated.

Could potentially be carried out by clinical nurse specialist.

2 Locally Advanced NSCLC

2.1 Background

Patients who have locally advanced disease (Stage IIIA and IIIB dry) should be treated with concurrent chemoradiotherapy where possible as this improves outcomes (from 13 months to 15-17 months, 5 year survival 14-16%)[2].

However, there is a price to pay in terms of toxicity (mainly increased oesophagitis, grade 3-4 in 25%) and patients need to be appropriately selected:

  • Good performance status (0-1)
  • Adequate lung function
  • Good renal, hepatic and haematological function
  • Disease can be encompassed in radiotherapy field (usually <9.5cm)

2.2 Staging

If patients are being considered for radical therapy they require:

  • CT Scan of Chest and Abdomen
  • CT PET Scan
  • CT Brain scan
  • Bone scan

2.2.1 Treatment Regimen for Concurrent Chemoradiotherapy in NSCLC

Cisplatin 50mg/m2 day 1& 8 (28 day cycle) and etoposide 50mg/m2 days 1-5

Radiotherapy is given 45Gy in 25# OD over the first five weeks[2]

Total of 4 cycles of chemotherapy are give proving there are no signs of disease progression

Prophylactic ciprofloxacin 500mg bd with cycle 1 day 5-14

CT scanning should be carried out early in week 4 to assess response as in some cases surgery may be considered (needs careful review of scans with surgical team). If surgical intervention is not appropriate consider further radiotherapy, 16Gy in 18#, with no break.

Patients with locally advanced disease who are not eligible for concurrent treatment should receive sequential chemotherapy followed by radiotherapy or in some cases, surgery. CT scanning should be carried out after the 3rd cycle of chemotherapy to allow radiotherapy planning.The chemotherapy regimen is the same as for advanced disease (see section 3). In cases where the MDM plan is for neo-adjuvant chemotherapy followed by surgery repeat CT scanning should be repeated after the 2nd or 3rd cycle of chemotherapy depending on surgeon preference.

2.2.2 Follow up

Initially 1 month after treatment finishes, then as symptoms dictate (usually 1-3 months, QoL is paramount and if patient is well 3 months is satisfactory).

CXR at every other follow up or as clinically indicated.

Repeat CT scan as clinically indicated.

3 Advanced (Metastatic and Stage IIIB wet) NSCLC

3.1 Background

It is now established that there is a modest survival benefit (2-5 months) for platinum based chemotherapy compared to active supportive care alone for patients with advanced NSCLC. There is also evidence that single agent third generation drugs also improve survival by about 2 months. Perhaps more importantly, chemotherapy has been shown to improve quality of life. Furthermore, in trials examining patient reported symptoms, improvement in symptoms is higher than objective response rates in all studies, suggesting that palliation can be achieved with tumour shrinkage that does not meet the standard criteria for objective response.

3.11 Cisplatin versus Carboplatin

Cisplatin was used frequently in the 80’s and 90’s for the treatment of SCLC and NSCLC. Carboplatin, an analogue of Cisplatin, has a more favourable toxicity profile and can be successfully substituted for Cisplatin in certain situations. Carboplatin does not require prehydration and can be used in a wider range of patients, however more myelosuppression is documented. Most studies suggest that carboplatin is as efficacious as cisplatin but less toxic, however a recent meta-analysis in the JCO 2004 of 8 trials (2,948 patients) concluded that cisplatin-based chemotherapy produced higher response rate (30 v 24%, p<0.001) but the 5% survival advantage was not significant[3]. A subgroup analysis showed combination chemotherapy (cisplatin + new agent) yields 11% longer survival than carboplatin + same new agent (P =0.039).

3.12 Third Generation Chemotherapy Drugs

Third generation drugs (docetaxel, paclitaxel, vinorelbine and gemcitabine) have all been shown to be effective in NSCLC both as single agents and in combination, although no one drug has shown consistent superiority over the others when combined with platinum[4]. Interestingly, higher response rates do not always translate into improved survival.

3.13 Duration of Treatment

The optimum duration of therapy for patients with advanced NSCLC has not been identified. In many patients, treatment is limited by co-morbidities which affect their performance status and ability to tolerate chemotherapy. Most randomised phase III studies use 4 cycles of treatment, and of those studies which have looked at continuing treatment until disease progression, the average number of cycles received was still 4. However, no trial has answered whether patients who are responding to chemotherapy and tolerating it well will benefit from a longer duration of treatment.

3.14NICE Guidance

Patients of good performance status should be offered chemotherapy to improve QoL, improve survival and control disease. Chemotherapy should be with a third generation drug (docetaxel, paclitaxel, vinorelbine and gemcitabine) combined with cisplatin or carboplatin, taking account of toxicities, efficacy and convenience.

Patients who are unable to tolerate a platinum combination should be offered single agent chemotherapy with a third generation agent.

3.2 Treatment Regimens for advanced NSCLC

3.2.1 First Line Therapy in Advanced NSCLC
3.2.1.1Patient selection

Patients with locally advanced (not suitable for concurrent chemoradiotherapy) and metastatic disease should be considered for chemotherapy providing they demonstrate:

  • Adequate performance status (ECOG PS 0/1, but to be considered in those of ECOG PS 2)
  • Adequate renal function (Cr Cl >50), liver and bone marrow function
3.2.1.2 Staging
  • Baseline CXR pre chemotherapy for comparison during treatment
  • CT Scan of chest and upper abdomen
  • Bone scan if symptomatic
  • CT Brain scan if symptomatic
3.2.1.3 Management
  • CXR at least prior to every 2nd cycle of chemotherapy to ensure no signs of disease progression (if disease progression demonstrated stop chemotherapy)
  • Post treatment CT scan of chest and abdomen
  • after 4 cycles for those with advanced/metastatic disease
  • after 3 cycles for those with locally advanced disease to allow for XRT planning
  • Consider XRT for patients with advanced/metastatic disease if symptomatic.
3.2.1.4 Treatment Regimen

Gemcitabine 1250mg/m2 D1 & D8 & carboplatin AUC5 D1[5]

21 day cycle

4 cycles planned.

Prophylactic ciprofloxacin 500mg bd with cycle 1 day 5-14

Carboplatin (AUC5 Day 1) and paclitaxel (175mg/m2 Day 1) [6]can be considered for as an alternative for patients who have to travel long distances for treatment or where there is pressure to reduce the number of day 8 treatments.

Patients with good performance statuswho have adequate renal function (CrCl >60ml/min) should be considered for cisplatin rather than carboplatin at 80mg/m2 D1 in combination with gemcitabine[7]. Given the higher response rates observed with cisplatin, patients who are being considered for resection following chemotherapy should be considered for cisplatin which can be given in combination with docetaxel [4]..

Patients who are unable to tolerate a platinum combination should be offered a single third generation agent with gemcitabine 1000mg/m2 D1,8 &15 (28 day cycle) [8]or vinorelbine 30mg/m2 weekly[9].

3.2.1.5 Follow Up

Follow up initially for scan results, then as symptoms dictate (usually 1-3 months, QoL is paramount and if patient is well 3 months is satisfactory).

CXR at every other follow up or as clinically indicated.

Repeat CT scan as clinically indicated.

3.2.2 Second Line Therapy for NSCLC

Docetaxel has been used as second line therapy following platinum and has shown efficacy in terms of improved QoL and survival benefit (2 months). ASCO and NICE guidance is that docetaxel should be considered for second line therapy in patients who have progressed on first line platinum based therapy and are of good performance status.

Recently NICE guidance has recommended Erlotinib, within its licensed indication, as an alternative to docetaxel as a second-line treatment option for patients with non-small-cell lung cancer (NSCLC) only on the basis that it is provided by the manufacturer at an overall treatment cost (including administration, adverse events and monitoring costs) equal to that of docetaxel.

3.2.2.1Patient selection
  • Adequate performance status (ECOG PS 0-2)
3.2.2.2 Management
  • CT scan of thorax and upper abdomen before cycle 1, after cycle 2 and thereafter every 2-3 cycles
  • CXR required prior to each cycle
  • Careful toxicity assessment prior to each cycle
  • If signs of disease progression stop treatment

3.2.2.2 Treatment Regimen

Erlotinib 150mg PO daily [10]

28 day cycle

Continue until progression or intolerable toxicity.

Or

Docetaxel 75mg/m2 D1[11]

21 day cycle

4 cycles planned.

Prophylactic ciprofloxacin 500mg bd with cycle 1 day 5-14

4. Chemotherapy Guidelines for SCLC

4.1 Background

Small cell lung cancer is characterised by its propensity for early metastases and a rapid doubling time. Around 15% of lung cancers are small cell and around 40% of cases are limited stage (LS) (can be encompassed by a single tolerable radiotherapy port). In view of its aggressive nature, surgery is not usually considered part of the treatment algorithm. Patients who are diagnosed following lung resection should still receive post-operative chemotherapy. It is an extremely chemosensitive disease with response rates to first line treatment in the order of 70-90%.

Performance status is the most important predictor of prognosis, however several factors should be taken into account when considering prognosis.

Manchester Score

A good prognosis is predicted by a score of 0-1, a poor prognosis is predicted by 3 or more of the following factors:

  • PS >1
  • Extensive disease
  • Low sodium
  • Elevated Alkaline Phosphatase
  • Elevated LDH

Studies in the 70’s and 80’s clearly demonstrated that combination chemotherapy was superior to single-agent therapy. For limited stage (LS) disease chemotherapy should be combined with radiotherapy (either concurrent or sequential) to improve outcomes.

Patients with good prognosis (Manchester score 0-1) who have limited stage disease have a 20% 5 year survival (which is a surrogate for cure in SCLC). Patients with extensive stage disease have a median survival of 6-12 months (depending on other prognostic factors).

Prophylactic cranial irradiation (PCI) significantly improves survival and reduces incidence of brain metastases in LS and ES patients who achieve at least a partial response to treatment[12, 13].

4.2 Staging

  • CT Scan of chest and abdomen
  • Bone scan
  • CT Brain scan

4.3 First Line Treatment of SCLC

Several studies have compared two commonly used regimens: cisplatin/etoposide and vincristine/doxorubicin /cyclophosphamide. Early studies suggested that the two regimens have equal efficacy, however, a meta-analysis of 4054 patients from 19 trials showed that platinum containing regimens are superior in terms of response rates and survival[14]. Platinum/etoposide regimens are now the treatment of choice for patients who can tolerate platinum with anthracyclines based regimens reserved for those who cannot.

Most of the trial evidence is for cisplatin based regimens rather than carboplatin and in the UK the pragmatic view is generally taken that cisplatin is used when survival is the main aim (limited stage, good prognosis), and carboplatin when the treatment is palliative.

Consider concurrent chemoradiotherapy in patients who have:

  • limited stage disease
  • good performance status
  • adequate lung function
  • adequate bone marrow, liver and renal function
4.3.1 Treatment Regimen for Concurrent Chemoradiotherapy

Cisplatin 75 mg/m2 day 1 & etoposide 100mg/m2 day 1-3

21 day cycle 4-6 cycles

Begin cycle 1 (if possible) or 2

Radiotherapy 45Gy in 30# BD over 3 weeks or 40-50Gy in 15-25# [15]

Prophylactic ciprofloxacin 500mg bd with each cycle day 5-14

4.3.2 Treatment Regimen for first Line Therapy

Cisplatin (80mg/m2) or Carboplatin (AUC 6) Day 1

etoposide 120mg/m2 day 1-3

6 cycles for limited stage/good prognosis (preferably cisplatin)

4 cycles for extensive stage/poor prognosis (usually carboplatin)

21 day cycle

Prophylactic ciprofloxacin 500mg bd with each cycle day 5-14

** oral etoposide may be used on day 2 & 3 when iv administration is not practicable. Oral dose is same mg/m2 as iv but twice daily (eg 100mg/m2 bd day 2&3). Note oral bioavailability is less predictable than iv.

4.3.3 Management
  • CT scan chest and abdomen
  • at baseline
  • after cycle 4 (even if planning to go to 6 cycles as this allows time for XRT planning )
  • CXR before each cycle
  • Consider consolidation thoracic radiotherapy and prophylactic cranial irradiation (PCI) in patients with at least partial response

Only consider other chemotherapy options if unable to tolerate platinum/etoposide. Management principals are the same.

  1. Vincristine (1.4mg/m2, max 2mg)/Adriamycin (50mg/m2)/Cyclophosphamide (800g/m2)[16]
  2. 4 cycles for patients unable to tolerate platinum/etoposide
  3. All given D1 of 21 day cycle
  4. CT scan pre and post chemo
  5. CXR before each cycle
  1. Adriamycin (40mg/m2)/Cyclophosphamide (1g/m2)/Etoposide (100mg/m2)
  2. 4 cycles for patients unable to tolerate platinum/etoposide or VAC (eg peripheral neuropathy)
  3. All given D1 of 21 day cycle
  4. CT scan pre and post chemo
  5. CXR before each cycle
  1. Single agent carboplatin AUC 5[17]
  2. For patients not fit enough for any of the above (RR 25%, 10% 1YS)
  3. Particularly those that it is hoped may be fit enough for CE with cycle 2
  1. Etoposide (120mg/m2 iv D1, 240mg/m2 oral D2-3)/ Vincristine (1.4mg/m2, max 2mg, D 1)[18]
  2. For patients not fit enough for any of the above (10% 1YS)
4.3.4 Follow Up

Initially one month after chemo for scan results. Then 6 weekly as SCLC is more aggressive than NSCLC until three months. Thereafter every 2-3 months according to symptoms.At 3 years 6 monthly. At 5-10 years annually.Note importance of patients contacting us for early appointment if symptoms occur.CXR every visit or as clinically indicated. No repeat scans unless clinically indicated.

4.4 Second Line Treatment of SCLC

Second line chemotherapy for SCLC should be reserved for those patients who have responded to 1st line treatment and have had at least 3 months between best response achieved with 1st line treatment and disease progression. The response rates with 2nd line treatments are lower and the balance of benefits and toxicity need to be carefully considered and discussed with each patient.

The options are clinical trials or:

  1. Re-challenging with further platinum/etoposide (regimens as for 1st line treatment – no more than 4 cycles, usually if TTP is 6 months or more)
  2. Anthracycline based treatment CAV or VAC (regimens as for 1st line treatment – no more than 4 cycles)

5. Treatment Guidelines for Malignant Pleural Mesothelioma

5.1 Background

Malignant pleural mesothelioma (MPM) is a rare and difficult tumour to treat with no widely accepted curative approaches. Treatment options are relatively limited. Patients with low volume epithelioid tumours, who are otherwise well, are potential candidates for radical surgery. British Thoracic Society Standards of care committee estimates that the number of these patients is small – about 1-5%.

The vast majority of patients are not suitable for a radical approach to treatment and are considered for surgical management of pleural fluid, port site radiotherapy and palliative chemotherapy.

Until recently there was no accepted standard chemotherapy treatment for the management of MPM. In 2003 Vogelzang reported a large (n=448) randomised phase 3 study which compared single agent cisplatin treatment to combination treatment with cisplatin and pemetrexed [19]. Median survival was improved from 9.3 months to 12.1 months (p=0.02), median time to progression was significantly longer (5.7 months versus 3.9 months, p=0.001) and response rates higher (41.3% versus 16.7%) in the pemetrexed arm. Toxicity was acceptable and manageable with vitamin supplementation and quality of life was improved.NICE approved pemetrexed for treatment of MPM in January 2008.

5.2 Treatment Regimen for Malignant Pleural Mesothelioma

Pemetrexed 500 mg/m2 day 1 and cisplatin 75 mg/m2 day 1

21 day Cycle

4-6 cycles

Hydroxocobalamin 1000 micrograms im 7 days before treatment starts and repeated every nine weeks until treatment is complete.

Folic acid 400mcg po od starting at least seven days before treatment starts, throughout treatment and for 21 days after last dose of pemetrexed.

5.2.1 Management
  • CT Scan of chest and abdomen
  • at baseline
  • after 4 cycles
  • CXR at baseline and at least every 2 cycles to look for disease progression

5.2.2 Follow Up

  • 3 monthly
  • Ensure palliative care input at an early stage

6. Supportive Therapies

  • Prophylatic antibiotics are routinely used with 1st cycle of treatment in patients with NSCLC or MPM to reduce the risk of neutropaenic sepsis [20]
  • In patients with SCLC prophylactic antibiotics should be given with each cycleto reduce the risk of neutropaenic fever and the number of infectious deaths[21]
  • Blood transfusions should be used to maintain Hb >9.0
  • G-CSF is only indicated for secondary prophylaxis in patients receiving treatment with curative intent

7. References

1.Douillard, J.Y., et al., Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol, 2006. 7(9): p. 719-27.