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(Chest. 1999;116:525S-530S.)
© 1999 American College of Chest Physicians

Management of Small Cell Lung Cancer*

Current State of the Art

David H. Johnson, MD

* From the Division of Medical Oncology, Vanderbilt University Medical School, Nashville, TN.

Correspondence to: David H. Johnson, MD, Professor of Medicine and Director, Division of Medical Oncology, Vanderbilt University Medical School, Nashville, TN 37232-5536; e-mail: david.johnson{at}mcmail.vanderbilt.edu


   Abstract
TOP
 Abstract
Introduction
 Chemotherapy
 Radiotherapy
 Conclusion
 References
 
Small cell lung cancer (SCLC) is a common malignancy that is rapidly fatal if left untreated, with most patients surviving < 6 months. Currently, patients with SCLC are treated with chemotherapy with or without thoracic radiotherapy. Randomized trials have demonstrated the superiority of multiagent regimens over single-agent therapies, with the combination of cisplatin and etoposide being the initial regimen of choice for most patients, regardless of stage at presentation. Dose escalation, weekly chemotherapy, alternating noncross-resistant chemotherapy, and maintenance chemotherapy have been evaluated in SCLC, with no convincing data to date demonstrating an advantage for these strategies over conventional treatment strategies. Second-line therapy may be effective in selected patients, depending on the interval between primary treatment and recurrence, response to primary therapy, and the agents used for initial treatment. Radiotherapy is generally accepted as an essential component of optimal management of limited-stage disease, although sequencing, timing, fractionation, dose, and field size remain less than adequately defined. Finally, the routine use of prophylactic cranial irradiation remains controversial, and currently should be reserved for patients in complete remission.


   Introduction
TOP
 Abstract
 Introduction
Chemotherapy
 Radiotherapy
 Conclusion
 References
 
Small cell lung cancer (SCLC) is a common malignancy seen almost exclusively in smokers.1 Unlike non-small cell lung cancer (NSCLC), SCLC is usually disseminated at diagnosis and is therefore not amenable to cure with surgery or thoracic radiotherapy (RT) alone. Indeed, if left untreated, SCLC is rapidly fatal, with most patients surviving < 6 months. With the recognition that this malignancy is chemotherapy-responsive, considerable improvement in survival has been achieved during the past three decades.2 At present, virtually all patients are treated with some form of chemotherapy with or without RT, depending on the extent of disease at the time of diagnosis. In rare circumstances, surgery may still play a role in the management of this malignancy. Performance status and extent of disease remain the preeminent prognostic factors in SCLC and dictate the choice of therapy. This paper reviews current concepts in the management of SCLC.


   Chemotherapy
TOP
 Abstract
 Introduction
 Chemotherapy
Radiotherapy
 Conclusion
 References
 
Multiple chemotherapy agents possess single-agent activity against SCLC, including cyclophosphamide, doxorubicin, vincristine, etoposide, nitrogen mustard, nitrosureas, and others.1 Recently, several new drugs with unique mechanisms of action also have proved active against SCLC. Among the more interesting new agents are paclitaxel (Taxol; Bristol-Myers Squibb; Princeton, NJ) and the camptothecin derivatives irinotecan (Camptosar; Pharmacia and Upjohn; Bridgewater, NJ) and topotecan (Hycamtin; SmithKline Beecham; Pittsburgh, PA).3 4 These new drugs are presently undergoing investigation in combination with other active agents. Although the role of the newer agents in the management of SCLC remains undefined, it is likely that some will become important components of standard chemotherapy regimens in the near future.5

Randomized trials have demonstrated the superiority of multiagent regimens over single-agent therapies in SCLC.6 7 This includes single-agent oral etoposide in elderly or medically unfit patients.7 8 Although multiple regimens yield approximately equivalent survival results, the combination of cisplatin and etoposide (PE) appears to have the best therapeutic index with fewer episodes of life-threatening toxicities. For example, Ihde and colleagues9 reported a 2% incidence of grade 3 or 4 myelosuppression with "standard"-dose PE. With such a low incidence of life-threatening myelosuppression, hematopoietic growth factors would rarely be necessary.10 11 Except in rare circumstances, the addition of a third drug to this two-drug regimen has done little to improve overall efficacy. In general, two-drug regimens are associated with fewer severe toxicities and fewer septic deaths.12 13 14 15 Also, PE is more easily administered with concurrent RT than other combination regimens, making it the preferred regimen for patients who are candidates for thoracic RT. For all the aforementioned reasons, PE is the initial chemotherapy choice for most SCLC patients, regardless of stage at presentation. Nevertheless, other combination regimens retain a role in selected circumstances. For example, where preexisting renal dysfunction or neuropathy exists or aggressive hydration is problematic, carboplatin can be substituted for cisplatin without apparent loss of therapeutic efficacy.16 17 18 19

Dose Escalation
Dose escalation has not proved beneficial in the management of SCLC, regardless of initial stage. At least four prospective randomized trials failed to demonstrate improved survival for patients given higher than "standard" induction doses of commonly used chemotherapy agents (Table 1 ).9 20 21 22 23 24 Based on compelling preclinical data,25 Southeastern Cancer Study Group investigators compared high-dose cisplatin, doxorubicin, and vincristine (CAV) with standard-dose CAV.21 Although the complete response rate was increased in the high-dose arm, survival was not improved. Ihde et al9 24 compared high-dose PE with standard doses of these agents and also found no improvement in response rates or survival. The difference in toxicities, however, was impressive. Fewer than 5% of the patients receiving standard-dose PE experienced life-threatening hematologic toxicity compared with > 35% of those given high-dose therapy. Finally, the addition of colony-stimulating factors to increase dose delivery has not yet been proved advantageous.22 26


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  		Table 1. Dose Escalation in SCLC*

 
Late intensification therapy is a potential means by which kinetic resistance might be overcome.27 Presumably, as a tumor shrinks in response to initial chemotherapy, the number of cells actively cycling through the cell cycle increases. A dose reduction at this point would be counterproductive, whereas dose escalation might prove beneficial. Several groups have explored this strategy in SCLC without success,2 and in the only randomized trial conducted to date, patients receiving dose intensification had a median survival similar to that seen in patients maintained on standard-dose therapy.28 A recent report from Harvard, however, has rekindled interest in this strategy.29 It should be noted that patients entered into the latter trial were highly selected. Using very similar selection criteria, Johnson et al30 demonstrated equally prolonged survival in a subset of patients who received standard-dose therapy only.

In summary, there are no convincing data indicating that dose intensification improves survival duration beyond that achieved with conventional combination regimens. Most disappointing is the finding that median survival times reported from pilot studies of highly selected patients are not superior to those observed in much less rigidly selected patients enrolled in randomized studies of single-agent etoposide or teniposide. Dose-intensive therapy should be considered experimental at the present time.

Weekly Chemotherapy
Dose intensity can be increased by shortening the intervals between cycles of chemotherapy. Such a strategy has been used in SCLC with promising results in pilot studies.2 The most impressive results were obtained by the Vancouver group using cisplatin, vincristine, doxorubicin, and etoposide (CODE).31 In patients with extensive stage SCLC, these investigators reported a median survival of > 14 months and a 2-year survival of > 30%. Standard therapies typically yield median survivals of just 8 to 10 months and 2-year survival rates of <= 2% in such patients. Unfortunately, when CODE was prospectively compared with a standard regimen of CAV alternating with PE, no survival advantage was observed.32 Moreover, toxicity was much greater with the weekly regimen, including a higher incidence of treatment-related deaths. These results are similar to those reported by other groups who have prospectively compared weekly chemotherapy with every-3-week treatment (Table 2 ).33 34 35 Thus, there is no apparent advantage to administering weekly chemotherapy in patients with SCLC.


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  		Table 2. Weekly Chemotherapy in SCLC*

 
Alternating Non-Cross-Resistant Chemotherapy
Alternating non-cross-resistant chemotherapy has considerable theoretical appeal based on the tenets of Goldie et al.36 Unfortunately, several prospective trials have failed to confirm the clinical utility of this approach (Table 3 ).2 National Cancer Institute of Canada investigators demonstrated a modest and statistically superior survival in extensive stage SCLC patients given CAV alternating with PE compared with patients treated with CAV alone.37 However, two subsequent trials conducted in the United States and Japan failed to confirm these data.14 15 Furthermore, the US and Japanese trials failed to demonstrate true non-cross-resistance between CAV and PE compared with CAV treatment alone.


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  		Table 3. Alternating Non-Cross-Resistant Chemotherapy in Extensive Disease SCLC*

 
Maintenance Chemotherapy
The optimal duration of chemotherapy in SCLC remains controversial. In the trials mentioned above, duration of therapy ranged from a few months in most instances to > 1 year in some cases. However, the available data indicate that four to six cycles of chemotherapy is sufficient to achieve optimal outcome, regardless of response category or initial stage (Table 4 ).38 39 40 41 Although some reports indicate an improvement in disease-free survival with maintenance chemotherapy,42 overall survival is not improved with treatment beyond four to six courses of chemotherapy. Furthermore, quality of life is diminished with continued treatment.43 Recently, Eastern Cooperative Oncology Group investigators reported excellent 5-year survival results in limited stage SCLC using just four cycles of PE.44


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  		Table 4. Maintenance Chemotherapy in SCLC

 
Second-Line Chemotherapy
On relapse, some SCLC patients may still be in good physical condition and desire further treatment. Guidelines for treating such patients, however, are relatively scant.45 The success of second-line chemotherapy depends on multiple factors45 46 47 48 : • the interval between cessation of primary therapy and detection of recurrence, • the nature of the response to primary therapy, and • the composition of the primary chemotherapy.

The longer the interval from cessation of primary treatment to the beginning of "salvage" chemotherapy, the greater is the probability of response.49 50 In circumstances where > 12 months have elapsed since completion of induction chemotherapy, retreatment with the original drug regimen may produce a second tumor regression.46 In contrast, a short period between completion of induction therapy and recurrence usually portends a poor outcome, especially if the interval is <= 3 months. Patients who responded to primary chemotherapy are more likely to respond to second-line therapy.49 50 On the other hand, patients who progress during primary chemotherapy rarely respond to second-line therapy, regardless of the composition of the original treatment regimen. Among the newer agents with activity against SCLC, both topotecan and paclitaxel have demonstrated some potential activity as second-line therapy.51 52 However, as is true with most drugs administered in this setting, the activity of topotecan or paclitaxel wholly depends on the quality of the initial response and the time off chemotherapy.


   Radiotherapy
TOP
 Abstract
 Introduction
 Chemotherapy
 Radiotherapy
Conclusion
 References
 
In limited stage SCLC, thoracic RT is generally accepted as an essential component of optimal management. However, many aspects of RT delivery remain less than adequately defined, including sequencing, timing, fractionation, dose, and field size.

RT Sequencing
Chemotherapy and RT can be administered concurrently, sequentially, or in an alternating manner. To date, randomized trials have failed to adequately determine the optimal sequence in which these two modalities should be delivered.53 54 55 Using cisplatin-based chemotherapy, Takada and colleagues53 reported an impressive survival advantage for concomitant RT compared with RT delivered sequentially following completion of the same chemotherapy. Gregor et al,54 reporting for the European Organization for Research and Treatment of Cancer, found no difference in survival when RT was delivered in a sequential or alternating manner with cyclophosphamide-based chemotherapy. Similarly, French investigators observed no survival advantage for concomitant RT over alternating RT in a recently completed randomized trial that also employed cyclophosphamide-based chemotherapy.55 Based on these and other data, one can conclude that concurrent therapy is associated with improved survival but at a cost of increased toxicity, especially if administered with cyclophosphamide-based chemotherapy regimens. However, if RT is administered concomitantly with PE, the long-term toxicities appear to be relatively modest. Short-term toxicity consists primarily of esophagitis, which is manageable. Given the survival advantage associated with concomitant PE and RT, these toxicities seem acceptable.

RT Timing
The early administration of RT could potentially eliminate localized populations of chemotherapy-resistant tumors cells that might be responsible for treatment failure if permitted to disseminate systemically. If true, this would be an obvious advantage for early administration of RT. On the other hand, delayed RT could be advantageous because smaller treatment fields might be possible, which in turn could result in less host toxicity. The determination of optimal RT timing is complicated by many factors, including the composition of the chemotherapy regimen employed. At least one group has reported improved survival with the delayed administration of RT (Table 5 ),56 57 and a second group observed no survival disadvantage with delayed RT.58 Both groups used cyclophosphamide-based chemotherapy in their randomized trials. However, because recent studies seem to indicate a modest survival advantage with cisplatin-based chemotherapy, these studies may no longer be relevant. In contrast, National Cancer Institute of Canada investigators observed a superior survival with early administration of RT when delivered concomitantly with PE (Table 5) .59 Similar excellent survival results were achieved in a large intergroup trial in which RT was administered with the first cycle of chemotherapy.44 Collectively, these plus some additional data60 suggest early RT administration is preferable to delayed RT in SCLC, especially if PE is used rather than a cyclophosphamide-based regimen.


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  		Table 5. RT Timing in SCLC

 
RT Fractionation
There are a number of theoretical reasons why multiple daily fractions (MDFs) of irradiation might be preferable to once-daily irradiation in SCLC.61 First, because SCLC has no radiobiologic shoulder, smaller fraction sizes can be used, resulting in less damage to normal tissues. Second, the use of MDF RT may allow cells to redistribute to more sensitive phases of the cell cycle during the interval from the first to the second or subsequent dose of irradiation, thus enhancing cytotoxicity. In several pilot trials, MDF RT yielded very promising results, prompting Eastern Cooperative Oncology Group and the Radiation Treatment Oncology Group to undertake a prospective, randomized trial in which once-daily RT was compared with twice-daily RT.44 The updated results of this study indicate that a survival advantage exists for the twice-daily RT arm.62 With a median follow-up of > 7 years, the median survival of patients treated with twice-daily RT is 22.7 months, compared with 19 months for those in the once-daily RT arm. Two-year survival is 46.6% and 40.8%, respectively (p = 0.043). Both arms actually performed extremely well, which may be attributable to the concomitant use of RT and PE chemotherapy, as discussed previously. Local failure was greater in the once-daily RT arm (52% vs 36%; p = 0.058). These data indicate that improvement in local control translates into a modest survival advantage. Therefore, additional strategies to enhance local control should be investigated, including RT dose escalation and the use of three-dimensional treatment planning techniques.

Prophylactic Cranial Irradiation
The use of prophylactic cranial irradiation (PCI) in the routine management of SCLC remains somewhat controversial. While PCI can clearly reduce the incidence of CNS metastases, none of the randomized trials conducted to date has demonstrated an impact on overall survival.63 A meta-analysis of these data was reported last year, which may help address the issue of survival advantage. Furthermore, some reports suggest that PCI may result in late-developing neurotoxicity, manifested as mild to severe dementia, ataxia, attention deficits, and other CNS symptoms.64 Whether these neurologic abnormalities are the result of therapy, the underlying disease, or an interaction between the two is unknown. However, recent data seem to indicate the neurologic findings sometimes attributed to PCI may in fact be related to the underlying malignancy. For example, Komaki et al65 and Arriagada et al66 found cognitive dysfunction in > 90% of SCLC patients before they underwent PCI, and this dysfunction did not appear to worsen in any patients on completion of their therapy.

In general, PCI probably should be reserved for patients in complete remission because there is little evidence it provides any benefit in patients who fail to respond completely to systemic therapy.66 Furthermore, if used, PCI should probably be administered after completion of chemotherapy and not during its administration, as myelosuppression can be increased.


   Conclusion
TOP
 Abstract
 Introduction
 Chemotherapy
 Radiotherapy
 Conclusion
References
 
The current state-of-the-art management for SCLC remains cisplatin-based combination chemotherapy with or without RT. Although a variety of strategies have been evaluated to enhance response to chemotherapy, none has been demonstrated to be more effective than conventional therapy with a cisplatin-based regimen. RT remains a mainstay of therapy for limited-stage disease SCLC, and concurrent administration with PE may provide a survival advantage. Early administration of RT using MDF also seems to translate into a modest survival advantage. In general, however, PCI should only be used in patients in complete remission. Continued research is warranted to further evaluate the role of newer chemotherapy agents in the management of SCLC, as well as the value of alternative RT administration schedules in combination with these agents.


   Footnotes
 
Abbreviations: CAV = cyclophosphamide, doxorubicin, vincristine; CODE = cisplatin, vincristine, doxorubicin, etoposide; MDF = multiple daily fraction; NSCLC = non-small cell lung cancer; PCI = prophylactic cranial irradiation; PE = cisplatin, etoposide; RT = radiotherapy; SCLC = small cell lung cancer


   References
TOP
 Abstract
 Introduction
 Chemotherapy
 Radiotherapy
 Conclusion
 References
 

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