Options for first- and second-line therapy in small cell lung cancer — a workshop discussion

ELSEVIER

Lung CancerVolume41, Suppl.4 (2003)S37-S41 www.elsevier.com/locaWhmgcan

Options for first- and second-line therapy in small cell lung cancer - a workshop discussion Nick Thatcher a~*,John Eckardt b and Mark Green ’ a University of Manchester and Christie Hospital, Manchestel; UK b Division of Hematology/Oncology, St. John’s Mercy Medical Centel; St Louis, USA cDivision of Hematology/Oncology, Medical University of South Carolina, Charlston, USA

Abstract

In a case study-based workshop, physicians were asked to discuss various aspects of patient management in small cell lung cancer (SCLC). For first-line chemotherapy, most investigators recommended treatment with etoposide/cisplatin, with possible dosing variations according to tolerability and convenience. In France (but not elsewhere), medical oncologists tend to use a four-drug regimen (etoposide/cisplatin/cyclophosphamide/epirubicin), based on the results of an extensive-stageSCLC trial. Alternative first-line regimens, such as vincristine/ifosfamide/carboplatin/etoposide (VICE) and topotecan/platinum, are currently being explored. Options for therapy in patients with recurrent disease are more varied, although there was consensusthat active treatment at relapse should be considered. Regimens include topotecan (alone or in combination), cyclophosphamide/doxorubicin/vincristine (CAV) and re-induction with the earlier first-line agents. Studies are also investigating the potential benefits of other combinations, including topotecan/vinorelbine and paclitaxel/carboplatin. For patients with relapsedextensive-stageSCLC and brain metastases,whole brain radiation therapy was considered appropriate for both palliative and therapeutic reasons.The potential role of combination therapy with topotecan/temozolomide, both of which crossthe blood-brain barrier, is currently being investigated. 0 2003 ElsevierScienceIreland Ltd. All rights reserved. Keywords:

Brain metastases;Combination; First-line; second-line; Small cell lung cancer

1. Introduction The workshop section of the investigator meeting was run as three parallel sessions in which the investigators

discussed various aspects of patient management in SCLC, based around a number of case studies. Topics for discussion included choice of first-line therapy for patients with good or poor performance status and extensive disease, and for those with complications such as liver dysfunction. Investigators were also asked to present their views on the use and timing of radiotherapy, and their choice of chemotherapy, in a relatively young patient with relapsed extensive disease. The potential place of topotecan and various novel regimens in first- or second-line disease management was also considered. This paper represents a summary of the investigators’ opinions and conclusions. * Correspondingauthor.Tel: +44 (0) 161 446 3000; Fax: +44 (0) 161446 3299.

2. Chemotherapy recommendations: performance status

patients with good

2.1. Etoposide plus cisplatin

For the relatively young patient described in Table 1, who has a good performance status despite the presence of liver metastases, most investigators agreed that they would

use etoposide plus cisplatin as their first-line choice of chemotherapy, with possible dosing variations according to patient tolerability and convenience. Although cisplatin is generally more toxic than carboplatin in terms of nausea, vomiting and neuro- or ototoxicity, it is less myelosuppressive and is usually preferred to carboplatin as initial therapy

in lung cancer patients. Etoposide regimens are reasonably flexible, for example the drug may be given intravenously for 2 days, with a double dose orally on day 3, or it may be given at the same daily intravenous (iv) dose over 3 days. For cisplatin, the usual

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Case study metastases

1 -

patient

with

good

performance

status

despite

liver

Patient: 50-year-old male college professor. Presenting features: cough and hemoptysis, with a 4 kg weight loss from baseline weight of 80 kg over previous 2-month period. History: has smoked two packets of cigarettes per day for 30 years. Physical examination: rhonchi in both lung fields, liver enlarged and palpable 4 cm below the costal margin. Chest X-ray: 4 x 5 cm mass in right upper lobe. Bronchoscopy: narrowing of the right upper lobe bronchus. Histology: biopsy reveals SCLC. Abdominal CT scan: four nodules in the liver consistent with metastatic SCLC. Cranial MRl scan: normal. Laboratory analysis: Hb 11 g/dl; AP, SGGT and SGPT slightly elevated; bilirubin normal. ECOG performance status: 1. CT = computed tomography; Hb = hemoglobin; AP = alkaline phosphatase; MRI = magnetic resonance imaging; SGGT = serum glutamicoxalacetic transaminase; SGPT = serum glutamic-pyruvic transaminase.

dose range is 60-80 mg/m* by iv infusion; however, the clinicians agreed that, in their experience, the dose can be reduced to 40 mg/m2 if necessary for tolerability with no apparent loss of efficacy. It is recommended that etoposide plus cisplatin be given for four to six courses. Patients should be monitored for signs and symptoms of neurotoxicity or other severe toxicities and switched to alternative therapies if necessary. 2.2. Novel regimens 2.2.1. Front-line therapy

One of the newer potential front-line regimens consists of vincristine, ifosfamide, carboplatin and etoposide (VICE). A UK MRC study of VICE versus standard-practice chemotherapy, including cyclophosphamide/doxorubicin/etoposide (CDE) or etoposide/cisplatin regimens, in patients with good performance status and extensive or limited disease, showed median survivals of 15.3 months versus 11.6 months, respectively [ 11. Combination therapy with topotecan plus paclitaxel as front-line treatment for SCLC may also be an option, as described by Greco [2] in this supplement. Paclitaxel plus carboplatin is another potential alternative regimen that has been extensively investigated in non-small cell lung cancer (NSCLC), but requires further study in SCLC. 2.2.2. Second-line therapy

There are a number of standard second-line therapy options for patients with SCLC. Choice of regimen depends on several factors, including the patient’s performance status, the interval since prior treatment and patient preference. Three-drug regimens consisting of cyclophosphamide/doxorubicin/vincristine (CAV) or cyclophosphamide/doxorubi-

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cin/etoposide (CDE) are used by some clinicians because of patient convenience, since only one visit is required every 21 days. However, their use may be limited by toxicity, particularly myelosuppression. There is evidence that single-agent topotecan 1.5 mg/m’ for 5 days every 21 days may be at least as effective as CAV in patients with recurrent SCLC [31, as described in more detail in this supplement [4]. For patients with good performance status (1 or 2) not responding to first-line treatment, it was also suggested that single-agent topotecan may be used at the lower dose of 1 mg/m2 daily for 5 days for one or two cycles. Finally, if the patient responded well to first-line therapy, such as etoposide plus cisplatin, with an interval of at least 1 year before relapse, most clinicians agreed that the initial regimen might usefully be tried again.

3. Chemotherapy recommendations: performance status

patients with poor

3. I. General recommendations

Despite the potential toxicity, very few patients are unsuitable for cisplatin therapy, even those with poor performance status. Therefore, rather than considering an alternative treatment regimen immediately, low-dose cisplatin (20-40 mg/m*) with reduced-dose etoposide may be an option although there appears to be no data on this approach in the literature. Patients with neuropathy and/or renal failure, however, may benefit from switching to carboplatin instead of cisplatin, individualizing the dose using the area under the concentration-versus-time curve (AUC) formula. CAV may also be an option in some patients, with careful monitoring for hematologic toxicity as it is important in patients with poor performance status. Topotecan may have a place as a first-line option in these patients, following further studies evaluating its role in patients with performance status 2 or 3. 3.2. Patients with impaired liver function

Treatment options vary for patients with impaired liver function, depending on the cause and severity of the dysfunction. If the liver impairment is due to the tumor, for example, it may be possible to use the same treatment as in patients without liver dysfunction but with additional supportive care. For patients with chronic hepatitis from other causes, the same treatment could be used but with reduced starting doses. The clinicians agreed that topotecan is a good choice even for patients with marked liver dysfunction, including inherited conditions such as Gilbert’s syndrome, and appears to be better tolerated than irinotecan in this respect. In patients with mild-to-moderate hepatic impairment, topotecan may be dosed without reference to liver function tests,

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whereas irinotecan dosing must be adjusted appropriately (irinotecan and topotecan SmFCs).

Table 2 Case study 2 - patient with extensive disease

3.3. Elderly patients

Patient: 61-year-old male car dealer. Presenting features: cough, some fatigue, 6-71b weight loss from usual weight of 217 lb. History: 60-pack year smoking history. Physical examination: chest examination reveals a prolonged expiratory phase but no dullness to percussion or abnormalities of ausculatation, liver edge palpable 3 cm below the right costal margin. Chest X-ray: right hilar mass. CT scan: irregular 2.5 cm medial right lung mass with bulky hilar and mediastinal adenopathy but no vena caval obstruction; 4 cm left adrenal mass very suggestive of metastatic tumor; three liver lesions, ranging from l-3 cm in diameter, also very consistent with metastatic tumor. Bronchoscopy: reveals SCLC. Cranial MRI scan: normal. Laboratory analysis: Hb 12.2 g/dl, otherwise normal, including measures of renal and hepatic function. ECOG performance status: 1

At least in the UK and USA, elderly is generally defined as 65 years of age or older on grounds of health-economic issues (such as retirement and pensions), but the data indicate that age is not a prognostic indicator. There was a strong consensus that patients should not be under-treated because of older age, and that their performance status and other prognostic indicators are more important considerations. It may, however. be necessary to reduce the dose of etoposide if there are other concerns in addition to age. It should be remembered that lung cancer patients enrolled in drug trials tend to be about 10 years younger than those in real life. More studies are needed to assess treatment responses and tolerability in older populations. 3.4. Oral versus intravenous therapy

There is a perception that oral agents may be weaker than iv agents, but this appears to be changing as new active oral cytotoxic agents are introduced. The acceptance of oral irinotecan, navelbine and etoposide in some countries indicates that oral formulations are viewed as effective methods of administering cytotoxic treatment. From the point of view of patient convenience, oral dosing of an agent such as topotecan would be useful in first-line combinations and could be especially useful in the relapsed or palliative setting. Innovative regimens may be used, in which the first dose of topotecan is given intravenously and then treatment is continued orally at home. Oral dosing of topotecan should be based on body surface area and not a flat dose. The results of a study comparing oral topotecan with etoposide plus platinum in SCLC (anticipated towards the end of 2003) will provide more evidence.

4. Therapeutic recommendations with good performance status

in extensive disease

4.1. Biopsies

Tissue biopsies of metastases may not always be appropriate, particularly if the clinical picture already indicates widespread involvement. For a patient such as the man described in Table 2, for example, it was generally agreed that adrenal and/or liver biopsies would not be appropriate because there was more than one lesion, strongly suggestive of extensive disease. However, if the only obvious lesion was an adrenal mass, it was felt that a biopsy would be appropriate in order to determine whether it was an adenoma or metastatic disease.

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CT = computed tomography; MRI = magnetic resonance imaging; Hb = hemoglobin.

4.2. First-line chemotherapy

It was agreed that two-drug therapy would be appropriate first-line treatment for this patient, using either etoposide/cisplatin or etoposide/carboplatin for four to six cycles, depending on response and tolerability. There was some variation in the doses recommended by different physicians, with a range of 60-80 mg/m2 for cisplatin and loo-120 mg/m* for etoposide. Studies are ongoing to determine whether topotecan/cisplatin may be active as first-line therapy in SCLC, as discussed by Greco in this supplement [2]. Results in terms of response and survival are still awaited. However, myelosuppressive toxicity appears to be minimized by reducing the dose of both agents and by administering cisplatin on the last rather than the first day of topotecan treatment. Most physicians would not use three-drug therapy initially, although a French study by Pujol and colleagues [5] has demonstrated a survival benefit with four-drug therapy (etoposide/cisplatin/cyclophosphamide/epirubicin) compared with etoposide/cisplatin in 226 patients with extensive SCLC and good performance status (O-2) [6]. In this study, l-year survival rates were 40% and 29%, respectively, and l&month survival rates were 18% and 9%. In this workshop, it was observed that chest clinicians in France still tend to use the two-drug regimen while French medical oncologists now use the four-drug regimen. 4.3. Radiotherapy

In the context of a complete response of systemic disease, with or without complete response in the chest, there are data suggesting that consolidative radiotherapy may be

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beneficial [7]. However, most physicians still do not use consolidative chest or brain radiotherapy as a general rule. Nevertheless, they may consider it if the patient has an excellent response with relatively low bulk disease. Palliative radiotherapy for local disease was considered appropriate for most patients. 4.4. Second-line chemotherapy Patients who respond to first-line therapy with etoposide/platinum but relapse within l-2 months generally have a worse prognosis than those who relapse later. However, time to relapse does not usually play a major role in decision-making with regard to second-line therapy unless there is an interval of around 12 months or more, in which case first-line therapy is often re-applied. For patients with extensive disease who relapse in less than a year, trials are ongoing to identify novel treatment regimens that are effective but relatively non-toxic in order to maintain quality of life as far as possible. There are data suggesting that a combination of topotecan/vinorelbine may be active in patients with recurrent or metastatic NSCLC. In a phase I/II trial, iv topotecan was given at a dose of 0.5-1.0 mg/m2 for 5 days, with iv vinorelbine 20-30 mg/m2 on days 1 and 5, in 21-day cycles [8]. With granulocyte colony-stimulating factor (G-CSF) support, dose-limiting toxicity had not been reached at the time of publication, and preliminary analysis showed an overall clinical response rate of 42% among 29 patients enrolled to date. However, this combination is not yet considered an option in SCLC. Three-drug regimens are not generally used as secondline therapy as a number of studies have demonstrated no benefit and increased toxicity compared with two-drug regimens [9]. However, clinical evidence from novel regimens being studied in the future may change this picture. The French four-drug regimen (etoposide/cisplatin/ cyclophosphamide/epirubicin) referred to above may be active but again does not appear to be used widely. Other regimens, for example those that include carboplatin, ifosfamide and etoposide, may be options in the future. Further studies need to be done to clarify their efficacy compared with standard regimens (such as etoposide/cisplatin) and novel regimens (such as irinotecan or topotecan/platinum), including those using oral topotecan.

5. Treatment of relapsed, extensive SCLC 5.1. Radiotherapy For a patient such as the one described in Table 3 young, with relatively early relapse after initial response and extensive disease, including brain metastases - it was considered that whole brain radiation therapy (WBRT) should be given early, either together with or followed

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Table 3 Case study 3 - patient who relapses early with extensive disease Patient: 48-year-old female postal worker. single mother of two teenagers. Initial diagnosis and management: limited-stage SCLC in left lung, achieved complete remission with four cycles of etoposide/carboplatin and thoracic radiotherapy. Presenting features at recurrence: 5 monthsafter completionof initial therapy, presents with cough, shortness of breath and occasional headaches. Physical examination: unremarkable. Neurological examination: non-focal. Thoracic CT scan: two new lesions outside of her radiation ports. Cranial MRI scan: two 1 cm lesions in the cortex with minimal edema. Laboratory analysis: Hb 11.5 g/d], WBC 4900 cells/mm3, neutrophils 70%, platelets 156,OOO/mm-‘,otherwise unremarkable. Dexametbasone treatment begun, whole brain radiation therapy being considered. CT = computed tomography; MRI = magnetic resonance imaging: Hb = hemoglobin: WBC = white blood cells.

by chemotherapy. Early WBRT was considered appropriate for both palliative and therapeutic reasons, focusing on quality of life as well as any potential survival advantage. 5.2. Chemotherapy For chemotherapy following WBRT in this patient, retreatment with etoposide/platinum was considered an option in view of the 5-month interval since her initial treatment. Cisplatin was considered to be preferable to carboplatin in this setting because of its lower propensity to produce hematologic toxicity, particularly if an appropriate dose is used (e.g. 60-75 mg/m2 daily every 3 weeks, possibly divided into three doses per day). Alternatively, it was felt that topotecan/taxane (e.g. taxane on days 1 and 8, with topotecan on days 1-3 or both drugs on days 1 and 8) may be appropriate in order to provide symptomatic relief, to try and improve this young patient’s comfort and quality of life. There are also some interesting data on paclitaxel/carboplatin as second-line therapy in patients with extensivestage SCLC who were refractory to a variety of different first-line regimens. In a Greek multicenter phase II study, 32 patients refractory to either etoposide/cisplatin or CAV were treated with paclitaxel 200 mg/m2 on day 1 and carboplatin AUC6 on day 2 in 4-week cycles [lo]. The treatment was considered to be generally well tolerated, although grade 314 neutropenia occurred in 37% of patients and the overall response rate was 25% (one complete and seven partial responses). A much higher response rate of 73.5% was reported in a Dutch phase II trial, in which 35 patients who had relapsed within 3 months after first-line treatment (cyclophosphamide/doxorubicin/etoposide) were treated with paclitaxel 175 mg/m2 by 3-hour infusion followed by a

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30-minttte infUSiOn of carboplatin (AUC7) once every 3 weeks for five cycles [ 111. Of the 25 responses, two were complete and 23 were partial responses. Again, toxicity was considered to be mild, with grade 314 hematologic toxicity reported in up to 27% of patients. Further studies are needed to confirm these results and to clarify the optimal treatment schedule. Whatever the choice of second-line chemotherapy, most investigators said they would give four to six cycles of treatment, depending on response and tolerability. If a single agent were to be used, weekly dosing with topotecan, possibly oral topotecan, was considered an interesting possibility. If chemotherapy were to be given concurrently with WBRT, there was a strong consensus that single-agent topotecan (oral if available) would be the treatment of choice, particularly as it crosses the blood-brain barrier [ 12,131. A phase I study has also been carried out looking at a combination of temozolomide/topotecan in a mixed population of relapsed cancer patients [ 141. This combination was chosen because, like topotecan, temozolomide crosses the blood-brain barrier very efficiently [ 1.51. Twenty-five patients with NSCLC, sarcoma, rectal, breast, head and neck cancer, or melanoma were included in the trial and treated with topotecan 1.0-1.5 mg/m2 plus temozolomide 50-200 mg/m2 for 5 days. Dose-limiting febrile neutropenia was observed in two of five patients treated with the highest doses. At the dose levels recommended for subsequent phase II studies (topotecan 1.5 mg/m2 plus temozolomide 150 mg/m2), treatment was reasonably well tolerated in terms of myelosuppression. A follow-up study will assess daily temozolomide with weekly topotecan. There are no studies so far looking at this combination specifically in SCLC patients. For patients who relapse after WBRT, it was felt that options were limited. There are some data in the literature on intrathecal therapy for lung cancer-related brain metastases [16,17], but most of the investigators believed that such treatment was of little benefit. 5.3. Patient support

In the context of relapsed extensive-stage SCLC, the need for appropriate patient support becomes even more important. When a patient such as the one described in Table 3 asks about her survival prospects, it was felt to be important to tell her the statistics but also to give her some hope as well as reassurance about symptomatic relief. If patients wish to explore alternative medicines (e.g. neutraceuticals), it was considered important to be supportive as well as cautionary in order to maintain the patient’s trust and openness.

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