Microcitoma (Small Cell Lung Cancer)

6 TREATMENT

6.1Treatment of localized SCLC, STAGE I

6.1.1 Prognosis
One percent of patients with small cell lung cancer will be found in stage I. The endpoint of treatment in this setting of patients is cure, which can reach 60% of cases. Cure rate is related to primary tumor extension, being 60% in T1N0 and 28% in T2N0 (6.XLIX).

6.1.2 Treatment strategy
Standard treatment includes chemotherapy on a type C basis. In most clinical centers surgery (before or after chemotherapy) is more and more included in standard treatment strategy for operable patients, on a type C basis (6.XLIX); otherwise, radiation therapy is standard treatment in unoperable patients on a type R basis. It is possible that selected patients may be cured with primary tumor resection and mediastinal lymphadenectomy alone, but since 1990 most oncologists would recommend adjuvant combination chemotherapy even in resected cases, since a survival advantage was observed in historical series. Surgical mortality (0-10%) or morbidity are similar to those reported for patients operated on for other diseases. Prophylactic cranial irradiation in patients in complete remission is appropriate for individual clinical use on a type R basis, since irradiation reduces the incidence of CNS relapse and complete responders constitute the subset of potentially curable patients. The 3-5 year-survival rates of post-surgery stage I patients range between 45 and 80% after resection and adjuvant chemotherapy. Local control at 5 years approach 90%. Since the probability of achieving local control with surgery alone in stage I patients is high, postoperative radiotherapy is not recommended in operated patients. Since it may be difficult to otherwise obtain a pathological diagnosis, diagnostic and therapeutical surgery is recommended for peripherally located lesions on a type R basis, but extensive mediastinal node dissection is not recommended if N2-N3 nodal involvement is discovered (surgical stage III).

6.1.3 Chemotherapy
Modern drug combinations include 2 or 3 among the most active agents. Each of these regimens will produce complete response in 50-70% of patients with limited disease and overall responses in approximately 80-90%.
A combination regimen for 6-8 cycles should be used as initial treatment. SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment. Combination standard options are:

PE:	cisplatin (75-100 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks carboplatin (300 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks
CAE:	cyclophosphamide (1000 mg/m2 day 1) + doxorubicin (40 mg/m2 day 1) + etoposide (100 mg/m2 day 1-3) q 3 weeks
ICE:	ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2d 1-3).

No regimen has been demonstrated to be superior to the others in terms of oncological outcomes although the 2-drug combination including cisplatin (carboplatin) and etoposide is widely accepted. Therefore the choice is to be done in relation to a better therapeutical index which may be in favor of this combination thanks to its reduced toxicity, particularly when combined with radiotherapy. A quality of life assessment of patients receiving weekly chemotherapy compared to that of patients receiving a 3-week-interval treatment demonstrated an advantage of the 3-week-interval option (6.XVII). This study demonstrated that quality of life may be individually critical for the chemotherapy choice.
Several randomised trials addressed the question of the role of alternating chemotherapy (6.XV, 6.XIV, 6.LIX, 6.XII). These studies randomising CAV (cyclophosphamide + doxorubicin + vincristine) regimen against alternating CAV/PE regimen provided mixed results. In one trial some benefit of the alternating regimen was observed in limited disease (2-year survival of 15% vs 20% for the alternating regimen) so that CAV/PE regimen in this setting of patients may be considered appropriate for individual clinical use on a type 3 level of evidence. A general observation was that between the two regimens there is a certain degree of cross-resistance which is higher with the sequence PE followed by CAV than the inverse sequence (CAV followed by PE).
Intensification of chemotherapy using weekly regimens does not improve outcome and should be considered still investigational.
Non cross-resistant drug consolidation (CAV for 6 cycles + thoracic radiation followed by PE) in responsive patients seems to improve duration of remission and overall survival but is still to be considered investigational. (6.XI)
The value of dose escalation with or without haemopoietic growth factors remains controversial and is not recommended in routine clinical practice. As of now randomised trials have not shown a survival benefit for doses above the conventional therapeutic range (6.XXI, 6.XXVI). The use of haemopoietic growth factors decreases the period of neutropenia and reduces the number of febrile episodes and the use of antibiotics. There are as yet no data to suggest that survival is improved.
Clinical guidelines for the use of growth factors have been recently published (6.I).
The duration of combination chemotherapy has been the subject of several trials (6.IV, 6.XV, 6.LIII). There is no survival advantage in continuing chemotherapy beyond 6-8 cycles.

6.2 Treatment of localized SCLC, STAGE II

6.2.1 Prognosis
Only less than 10% of cases will be diagnosed with stage II disease. Disease metastases are the most common cause of treatment failure, even in patients who present with limited disease. The endpoint of treatment in this setting of patients is cure, which can reach 20%-30% of cases. Cure probability is related to primary tumor extension being 10% in T2N1 and 30% in T1N1 (6.XLIX). In the pathological stage II, 3-5-year survival rates range between 15-50%.

6.2.2 Treatment strategy
Standard treatment is chemotherapy and radiotherapy on a type C basis, even though in many clinical centers surgery (before or after chemotherapy) is more and more resorted to, as a substitute for radiotherapy, in operable patients, on a type 3 level of evidence (6.XLIX). Indeed, in a randomised trial, surgery in responsive patients after induction chemotherapy failed to demonstrate any significant advantage over a chemo-radiation approach (6.XXX). In this study, however, there was a significant reduction (>50%) of the number of patients undergoing randomisation after induction therapy, and therefore any conclusion may be doubtful. Overall in literature there is some evidence of a reduction of locoregional relapses in patients undergoing surgical resection on comparison to those undergoing radiation therapy. One should notice that both surgery and radiation therapy should be reserved to fully ambulatory patients with adequate pulmonary function. Studies have not addressed the role of postoperative radiation therapy, and it can therefore be considered investigational or appropriate for individual clinical use on a type 3 level of evidence. Prophylactic cranial irradiation in patients in complete remission is appropriate for individual clinical use on a type 2 level of evidence, since irradiation reduces the incidence of CNS relapse. The use of very high dose chemotherapy with autologous bone marrow or peripheral stem cell reinfusion remains investigational both as initial induction treatment and as consolidation therapy after induction of complete response. Since it may be difficult to otherwise obtain a pathological diagnosis, diagnostic and therapeutical surgery is recommended for peripherally located lesions on a type R basis, but extensive mediastinal node dissection is not recommended if N2-N3 nodal involvement is discovered (surgical stage III).

6.2.3 Chemotherapy
Modern drug combinations include 2 or 3 among the most active agents. Each of these regimens will produce complete response in 50-70% of patients with limited disease and overall responses in approximately 80-90%.
A combination regimen for 6-8 cycles should be used as initial treatment. SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment. Combination standard options are:

PE:	cisplatin (75-100 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks carboplatin (300 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks
CAE:	cyclophosphamide (1000 mg/m2 day 1) + doxorubicin (40 mg/m2 day 1) + etoposide (100 mg/m2 day 1-3) q 3 weeks
ICE:	ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2d 1-3).

No regimen has been demonstrated to be superior to the others in terms of oncological outcomes although the 2-drug combination including cisplatin (carboplatin) and etoposide is widely accepted. Therefore the choice is to be done in relation to a better therapeutical index which may be in favor of this combination thanks to its reduced toxicity, particularly when combined with radiotherapy. A quality of life assessment of patients receiving weekly chemotherapy compared to that of patients receiving a 3-week-interval treatment demonstrated an advantage of the 3-week-interval option (6.XVII). This study demonstrated that quality of life may be individually critical for the chemotherapy choice.
Several randomised trials addressed the question of the role of alternating chemotherapy (6.XV, 6.XIV, 6.LIX, 6.XII). These studies randomising CAV (cyclophosphamide + doxorubicin + vincristine) regimen against alternating CAV/PE regimen provided mixed results. In one trial some benefit of the alternating regimen was observed in limited disease (2-year survival of 15% vs 20% for the alternating regimen) so that CAV/PE regimen in this setting of patients may be considered appropriate for individual clinical use on a type 3 level of evidence. A general observation was that between the two regimens there is a certain degree of cross-resistance which is higher with the sequence PE followed by CAV than the inverse sequence (CAV followed by PE).
Intensification of chemotherapy using weekly regimens does not improve outcome and should be considered still investigational.
Non cross-resistant drug consolidation (CAV for 6 cycles + thoracic radiation followed by PE) in responsive patients seems to improve duration of remission and overall survival but is still to be considered investigational. (6.XI)
The value of dose escalation with or without haemopoietic growth factors remains controversial and is not recommended in routine clinical practice.As of now randomised trials have not shown a survival benefit for doses above the conventional therapeutic range (6.XXI, 6.XXVI). The use of haemopoietic growth factors decreases the period of neutropenia and reduces the number of febrile episodes and the use of antibiotics. There are as yet no data to suggest that survival is improved. Clinical guidelines for the use of growth factors have been recently published (6.I). The duration of combination chemotherapy has been the subject of several trials (6.IV, 6.XV, 6.LIII). There is no survival advantage in continuing chemotherapy beyond 6-8 cycles.

6.2.4 Thoracic radiation therapy
Thoracic radiation added to chemotherapy improves survival by 3-7% (6.XXXVII, 6.LVIII). The timing of thoracic radiation is still debated, some studies showing a benefit of early radiation, others of later treatment. Concurrent chemo-radiotherapy seems to improve local and distant control and survival and may be appropriate for individual clinical use on a type 3 level of evidence (6.XXVII). Unfortunately the concurrent administration of chemo-radiation is more toxic than the sequential approach. No randomised evidence is available and the published meta-analysis could not identify significant differences between the sequential and non sequential approaches (concurrent or alternating radiotherapy) (6.XXXVII, 6.LVIII). A randomised trial addressing this question is ongoing (6.LIV). Loco-regional relapses remain a dominant failure site in limited-stage SCLC with a risk of 40-60% also after combination of thoracic radiotherapy with standard chemotherapy. Standard radiation treatment on a type C basis for limited-stage SCLC in curative settings is thoracic radiotherapy to a total dose of 50 Gy given with one daily 2 Gy fraction, 5 times per week. A boost of 10 Gy with 5x2 Gy per week to a reduced volume may be appropriate for individual clinical use if radiotherapy is given consecutive to chemotherapy. The concurrent administration of radiotherapy and chemotherapy causes more acute toxicity (esophagus and bone marrow) which may result in toxic deaths and suboptimal chemotherapy dose intensity and delays in radiation therapy. Total dose of radiotherapy is usually reduced to 45 Gy when given concurrently with chemotherapy. Three-dimensional treatment planning allows the optimization of beam directions, field shaping, tissue inhomogeneity corrections, and the selection of wedge filters on comparison with traditional planning. This enables minimization of the radiation doses and irradiated normal tissue volumes outside the target volume. Accelerated radiotherapy schedules or schedules with increased total doses >60 Gy in conventional fractionation are investigational. Hyperfractionation may allow some dose escalation although it is associated with greater toxicity (esophageal mucositis). It has been shown to be able to reduce local failure. No clear survival advantage has been observed (6.XXIII).

6.2.5 Prophylactic cranial radiation therapy
Prophylactic cranial irradiation is appropriate for individual clinical use on a type 3 level of evidence (6.III, 6.XXIX) in patients achieving a complete remission. In fact, in randomized trials prophylactic cranial irradiation decreased the risk of cerebral metastases threefold (from 30% to 10%) without altering survival rates. The potential of prophylactic cranial irradiation in terms of higher cure rate is limited to only 10% of patients. It has been suggested that cranial irradiation may increase neuropsychological syndromes and brain abnormalities as indicated by CT scan, even if in the majority of cases cognitive deficits are described in patients before starting any treatment including chemotherapy. These preexisting impairments have been associated with paraneoplastic phenomena. The most frequent impairments are in terms of decreased verbal memory, frontal lobe dysfunction and fine motor coordination disturbances. Patient characteristics (age, comorbidity), type of chemotherapy, concurrent chemo-radiotherapy, and high individual radiation fraction are variables which may increase the probability of such impairments. It is recommended to administer prophylactic cranial irradiation, if indicated after the end of chemotherapy (6.LVI). Parallel opposed lateral portals are used. 1- 6 MeV photons are appropriate. Care has to be taken that the entire brain, including the basal frontal and temporal lobes, be irradiated and that ocular lenses be spared. Total doses are limited by the risk of late normal tissue damage with impairment of the neuropsychological function. 24-30 Gy given with one 2-3 Gy fraction per day, 5 days per week for 2-3 weeks is conventional. In recent studies the selected dose is 24 Gy.

6.3 Treatment of localized SCLC, STAGE IIIA, IIIB

6.3.1 Treatment strategy
Chemotherapy combined with thoracic radiotherapy is the standard option on a type 1 level of evidence (6.XXXVII). Improvement of survival rates by surgery after induction chemotherapy followed by thoracic irradiation could not be demonstrated in comparison with chemo-radiotherapy alone. Therefore surgery after induction chemotherapy remains investigational for SCLC in these stages (6.XXX). The use of very high dose chemotherapy with autologous bone marrow or peripheral stem cell reinfusion remains investigational both as initial induction treatment and as consolidation therapy after induction of complete response. Prophylactic cranial irradiation in patients in complete remission is appropriate for individual clinical use on a type 2 level of evidence, since irradiation reduces the incidence of CNS relapse.

6.3.2 Chemotherapy
Modern drug combinations include 2 or 3 among the most active agents. Each of these regimens will produce complete response in 50-70% of patients with limited disease and overall response in approximately 80-90%. A combination regimen for 6-8 cycles should be used as initial treatment. SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment. Combination standard options are:

PE:	cisplatin (75-100 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks carboplatin (300 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks
CAE:	cyclophosphamide (1000 mg/m2 day 1) + doxorubicin (40 mg/m2 day 1) + etoposide (100 mg/m2 day 1-3) q 3 weeks
ICE:	ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2d 1-3).

No regimen has been demonstrated to be superior to the others in terms of oncological outcomes although the 2-drug combination including cisplatin (carboplatin) and etoposide is widely accepted. Therefore the choice is to be done in relation to a better therapeutical index which may be in favor of this combination thanks to its reduced toxicity, particularly when combined with radiotherapy. A quality of life assessment of patients receiving weekly chemotherapy compared to that of patients receiving a 3-week-interval treatment demonstrated an advantage of the 3-week-interval option (6.XVII). This study demonstrated that quality of life may be individually critical for the chemotherapy choice. Several randomised trials addressed the question of the role of alternating chemotherapy (6.XV, 6.XIV, 6.LIX, 6.XII). These studies randomising CAV (cyclophosphamide + doxorubicin + vincristine) regimen against alternating CAV/PE regimen provided mixed results. In one trial some benefit of the alternating regimen was observed in limited disease (2-year survival of 15% vs 20% for the alternating regimen) so that CAV/PE regimen in this setting of patients may be considered appropriate for individual clinical use on a type 3 level of evidence.
A general observation was that between the two regimens there is a certain degree of cross-resistance which is higher with the sequence PE followed by CAV than the inverse sequence (CAV followed by PE).
Intensification of chemotherapy using weekly regimens does not improve outcome and should be considered still investigational.
Non cross-resistant drug consolidation (CAV for 6 cycles + thoracic radiation followed by PE) in responsive patients seems to improve duration of remission and overall survival but is still to be considered investigational. (6.XI)
The value of dose escalation with or without haemopoietic growth factors remains controversial and is not recommended in routine clinical practice. As of now randomised trials have not shown a survival benefit for doses above the conventional therapeutic range (6.XXI, 6.XXVI). The use of haemopoietic growth factors decreases the period of neutropenia and reduces the number of febrile episodes and the use of antibiotics. There are as yet no data to suggest that survival is improved. Clinical guidelines for the use of growth factors have been recently published (6.I).
The duration of combination chemotherapy has been the subject of several trials (6.IV, 6.XV, 6.LIII). There is no survival advantage in continuing chemotherapy beyond 6-8 cycles.

6.3.3 Thoracic radiation therapy
Thoracic radiation added to chemotherapy improves survival by 3-7% (6.XXXVII, 6.LVIII). The timing of thoracic radiation is still debated, some studies showing a benefit of early radiation, others of later treatment. Concurrent chemo-radiotherapy seems to improve local and distant control and survival and may be appropriate for individual clinical use on a type 3 level of evidence (6.XXVII). Unfortunately the concurrent administration of chemo-radiation is more toxic than the sequential approach. No randomised evidence is available and the published meta-analysis could not identify significant differences between the sequential and non sequential approaches (concurrent or alternating radiotherapy) (6.XXXVII, 6.LVIII). A randomised trial addressing this question is ongoing (6.LIV). Loco-regional relapses remain a dominant failure site in limited-stage SCLC with a risk of 40-60% also after combination of thoracic radiotherapy with standard chemotherapy. Standard radiation treatment on a type C basis for limited-stage SCLC in curative settings is thoracic radiotherapy to a total dose of 50 Gy given with one daily 2 Gy fraction, 5 times per week. A boost of 10 Gy with 5x2 Gy per week to a reduced volume may be appropriate for individual clinical use if radiotherapy is given consecutive to chemotherapy. The concurrent administration of radiotherapy and chemotherapy causes more acute toxicity (esophagus and bone marrow) which may result in toxic deaths and suboptimal chemotherapy dose intensity and delays in radiation therapy. Total dose of radiotherapy is usually reduced to 45 Gy when given concurrently with chemotherapy. Three-dimensional treatment planning allows the optimization of beam directions, field shaping, tissue inhomogeneity corrections, and the selection of wedge filters on comparison with traditional planning. This enables minimization of the radiation doses and irradiated normal tissue volumes outside the target volume. Accelerated radiotherapy schedules or schedules with increased total doses >60 Gy in conventional fractionation are investigational. Hyperfractionation may allow some dose escalation although it is associated with greater toxicity (esophageal mucositis). It has been shown to be able to reduce local failure. No clear survival advantage has been observed (6.XXIII).

6.3.4 Prophylactic cranial radiation therapy
Prophylactic cranial irradiation is appropriate for individual clinical use on a type 2 level of evidence (6.III,6.XXIX) in patients achieving a complete remission. In fact, in randomized trials prophylactic cranial irradiation decreased the risk of cerebral metastases threefold (from 30% to 10%) without altering survival rates. The potential of prophylactic cranial irradiation in terms of higher cure rate is limited to only 10% of patients. It has been suggested that cranial irradiation may increase neuropsychological syndromesand brain abnormalities as indicated by CT scan, even if in the majority of cases cognitive deficits are described in patients before starting any treatment including chemotherapy. These preexisting impairments have been associated with paraneoplastic phenomena. The most frequent impairments are in terms of decreased verbal memory, frontal lobe dysfunction and fine motor coordination disturbances. Patient characteristics (age, comorbidity), type of chemotherapy, concurrent chemo-radiotherapy, and high individual radiation fraction are variables which may increase the probability of such impairments. Prophylactic cranial irradiation is recommended after the end of chemotherapy (6.LVI). Parallel opposed lateral portals are used. 1- 6 MeV photons are appropriate. Care has to be taken that the entire brain, including the basal frontal and temporal lobes, be irradiated and that ocular lenses be spared. Total doses are limited by the risk of late normal tissue damage with impairment of the neuropsychological function. 24-30 Gy given with one 2-3 Gy fraction per day, 5 days per week for 2-3 weeks is conventional. In recent studies the selected dose is 24 Gy.

6.4 Treatment of extensive disease, STAGE IV

6.4.1 Treatment strategy
The cure rate is so low in patients with extensive disease, that treatment must be considered palliative for most patients. Indeed, a few patients with extensive disease may be cured (overall survival at 5 years is less than 5%). Chemotherapy is able to improve intrathoracic symptoms in 50% of patients with pleural effusion, in 80% of patients with superior vena cava syndrome and in 70% of patients with atelectasis (1.5.2). A combination chemotherapy is therefore standard treatment on a type C basis. The combination of chest radiotherapy after chemotherapy is appropriate for individual clinical use on a type 3 level of evidence. It reduces progression in the chest without altering response rates, disease free survival nor survival. Smaller volumes are irradiated and higher doses per fractions can be given, unlike in curative settings. Prophylactic cranial irradiation may be appropriate for individual clinical use on a type R basis in selected patients, i.e. those gaining a complete response and with good performance status, since it is reasonable to believe that prophylactic cranial irradiation may delay the appearance of symptomatic CNS disease. In patients with synchronous CNS metastases at diagnosis, standard treatment is chemotherapy and radiation therapy on a type C basis. Since, in the clinical practice, radiation therapy may not be immediately available, initial chemotherapy may be followed by brain irradiation. Even if the concomitant association of corticosteroids may reduce the activity of chemotherapy at the CNS level, response rate may be above 50%. It has been observed that response may be achieved with the first cycle of chemotherapy with rapid improvement of neurological symptoms. One should notice that occasional patients presenting with isolated CNS metastases may have a good outcome. Palliative radiation therapy may be appropriate even for patients not responding to chemotherapy, depending on the performance status. Radiosurgical approach followed by adjuvant whole brain irradiation is appropriate for individual clinical use on a type 3 level of evidence (6.XLI). Local control (80%) seems to be superior to whole brain radiotherapy alone (60%). Symptoms of superior vena cava obstruction and painful bone metastases respond well to treatment. Patients with both painful thoracic vertebral metastasis and a positive vertebral bone scan have a high risk of spinal cord compression. Prophylactic radiation should be considered as appropriate for individual clinical use.

6.4.2 Chemotherapy
Modern drug combinations include 2 or 3 among the most active agents. In extensive disease patients, complete response rate is 10-15% and overall response is 60-70%. A combination regimen for 6-8 cycles should be used as initial treatment. SCLC is sensitive to alkylating agents such as cyclophosphamide and ifosfamide, platinum compounds (cisplatin and carboplatin), epipodophyllotoxins (etoposide and teniposide), anthracyclines such as doxorubicin and epirubicin, vinca alkaloids and methotrexate. Combination chemotherapy is superior to single-agent treatment. Combination standard options are:

PE:	cisplatin (75-100 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks carboplatin (300 mg/m2) + etoposide (100 mg/m2 day 1-3) q 3 weeks
CAE:	cyclophosphamide (1000 mg/m2 day 1) + doxorubicin (40 mg/m2 day 1) + etoposide (100 mg/m2 day 1-3) q 3 weeks
ICE:	ifosfamide (5000 mg/m2 day 1) + carboplatin (300-400 mg/m2 day 1) + etoposide (100-120 mg/m2d 1-3)

6.5 Treatment of relapsed SCLC

6.5.1 Isolated lung relapse or persistent disease
Tumour relapses to the lungs, as sole relapse site, or failing to respond to chemotherapy and radiotherapy, may be due to a different histology or a mixed tumor. A new biopsy may be therefore recommended. In such patients, without nodal involvement and other metastatic site, salvage surgery may be appropriate for individual clinical use on a type 3 level of evidence. In these highly selected patients a 5-year survival of approximately 20% can be achieved (6.XLVIII).

6.5.2 Relapsed/progressive disease on chemotherapy
Tumours which relapse or progress on chemotherapy seldom show clinically useful or lasting response to alternative drug combinations. Therefore, treatment with second line chemotherapy is appropriate for individual clinical use on a type R basis.

6.5.3 Relatively late relapse
Patients whose tumours relapse more than three months after first line chemotherapy may benefit from a reintroduction of the same regimen or from a different combination. Chemotherapy dose should not be increased to the point of toxicity in these patients or continued if response does not occur or is not sustained. Palliative radiotherapy may be appropriate for individual clinical use on a type R basis in patients with thoracic recurrences after chemotherapy if thoracic radiotherapy is not given in first line. Total doses of 10 Gy in one fraction or 17 Gy with 2 weekly fractions of 8.5 Gy, delivered through ap-pa fields including the primary site and mediastinal nodes, are adequate for patients with poor performance status (6.XXXIII). Thirty Gy with 10x3 Gy is also an accepted palliative schedule.

6.6 Treatment of synchronous tumors

6.6.1 Treatment strategy
In extensive-stage SCLC, where 2-year survival is rare, synchronous tumors need to be treated if symptomatic. In limited-stage SCLC, treatment of the fast growing SCLC has priority over the treatment of synchronous tumors with higher incidence, as cancer of the breast, the colon and rectum, or the uterus in females and carcinomas of the prostate, the colon and rectum or the bladder in males. If resectable, synchronous carcinomas should be resected after standard therapy for limited-stage SCLC. Non resectable synchronous tumors may either lead to a palliative treatment program or be treated by definitive radiotherapy alone or by combined radiotherapy and resection after attaining complete remission of the lung cancer by the standard therapy for limited-stage SCLC, if judged tolerable for the individual patient.

References

6.I
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6.II
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6.III
Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 1995; 87: 183- 190.

6.IV
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6.V
Borgelt B, Gelber R, Kramer S et al. The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980; 6:1-9.

6.VI
Bork E, Ersboll J, Dombernowsky P, Bergman B, Hansen M, Hansen HH. Teniposide and etoposide in previously untreated small cell lung cancer: a randomized study. J Clin Oncol 1991;9:1627-31.

6.VII
Coolen L, van den Eeckhout A, Deneffe G, Demedts M, Vansteenkiste J. Surgical treatment of small cell lung cancer. Eur J Cardio-Thor Surg 1995;9:59-64.

6.VIII
Coy P, Hodson DI, Murray N, Pater JL, Payne DG, Arnold A, et al. Patterns of failure following loco-regional radiotherapy in the treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys 1993; 28: 355-362.

6.IX
Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325: 164-170.

6.X
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6.XI
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6.XII
Evans WK, Feld R, Murray N, Willan A, Coy P, Osoba D et al. Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer. A multicenter, randomized clinical trial by the National Cancer Institute of Canada. Ann Int Med 1987;107:451-458.

6.XIII
Feld R, Evans WK, Coy P, et al. Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 1987; 5: 1401-1409.

6.XIV
Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T. Randomized trial of cyclophosphamide, doxorubicin and vincristine versus cisplatin and etoposide versus alternation of these regimens in small cell lung cancer. J Natl Cancer Inst 1991;83:855-861.

6.XV
Giaccone G, Dalesio O, McVie GJ, et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. J Clin Oncol 1993; 11: 1230-124.

6.XVI
Goodman GE, Crowley JJ, Blasco JC et al. Treatment of limited small cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a South West Oncology Group study. J Clin Oncol 1990;8:39-47.

6.XVII
Gower NH, Rudd RM, Ruiz de Elvira MC et al. Assessment of quality of life using a daily diary card in a randomised trial of chemotherapy in small cell lung cancer. Annals of Oncology 1995;6:575-580.

6.XVIII
Healy EA, Abner A. Thoracic and cranial radiotherapy for limited-stage small cell lung cancer. Chest 1995; 107: 249S-254S.

6.XIX
Higgins GA, Shields TW, Keehn RJ. The solitary pulmonary nodule. Arch Surg 1975; 110: 570-575.

6.XX
Ichinose Y, Hara N, Ohta M, Takamori S, Kawasaki M, Hata K. Comparison between resected and irradiated small cell lung cancer in patients in stages I through IIIa. Ann Thorac Surg 1992; 53: 95-100.

6.XXI
Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 1994; 12: 2022-2034.

6.XXII
Johnson DH, Einhorn LH, Birch R, et al. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1987; 5: 1731-1738.

6.XXIII
Johnson DH, Einhorn LH, Birch R, et al. A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1987; 5: 1731-1738.

6.XXIV
Joss RA, Bacchi M, Hurny C, et al. Early versus late alternating chemotherapy in small-cell lung cancer. Ann Oncol 1995; 6: 157-166.

6.XXV
Karrer K, Shields TW, Denck H, Hrabar B, Vogt-Moykopf I, Salzer GM. The importance of surgical and multimodality treatment for small cell bronchial carcinoma. J Thorac Cardiovasc Surg 1989;97: 168-76.

6.XXVI
Klasa RJ, Murray N, Coldman AJ. Dose-intensity meta-analysis of chemotherapy regimens in small cell lung cancer. J Clin Oncol 1991;9:499-508.

6.XXVII
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6.XXVIII
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6.L
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6.LIX
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� European School of Oncology, 1996

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