96 - Statistical Analysis
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 112 - Multimodality Therapy for Non Small-Cell Lung Cancer
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Chapter 112
Multimodality Therapy for Non Small-Cell Lung Cancer
Sunil Singhal
Joseph B. Shrager
Larry R. Kaiser
Although surgical resection for early, localized non small-cell lung cancer (NSCLC) is the only treatment that experience has shown to be curative in a high proportion of patients, even patients with stage Ia disease have 5-year survival rates of only approximately 70% when treated by surgery alone. Local recurrences do occur, but extrathoracic recurrence has continued to be the major problem. Autopsy studies by Martini and Flehinger (1987), as well as Gail (1984), Matthews (1973), and Feld (1984) and their colleagues, have shown that well over one-half of first recurrences are systemic. Clearly, other methods of therapy that can have benefit additive to that of surgical resection need to be considered. Adjuvant and neoadjuvant chemotherapy have the potential to reduce these rates of distant recurrence and thus improve the overall management of NSCLC. For early-stage disease, this potential has yet to be fulfilled; for later-stage disease, the use of multimodality therapies is promising but remains controversial.
Historically, fewer than 15% of all NSCLC patients have even been considered candidates for surgical resection. Neoadjuvant (preoperative) therapies, in particular, often with a component of radiation therapy, may allow potentially curative operation in patients who previously were considered nonsurgical and thus relegated to what have been for the most part palliative modalities.
Some definitions are in order before further discussion of multimodality therapies. Surgery may follow an induction regimen of chemotherapy, radiation, or combined chemoradiation, in which case the nonsurgical therapies are termed neoadjuvant treatments; surgery may precede chemotherapy, irradiation, or both, in which case the therapies are termed adjuvant treatments; or surgery may be sandwiched between some combination of chemotherapy and radiation therapy.
INDICATIONS FOR MULTIMODALITY TREATMENT
Stages I and II NSCLC have traditionally been managed by operation alone. However, the 5-year survival rate for clinical stages I and II ranges only from 50% to 80%. Although postoperative adjuvant therapy for stage II (N1) has been recommended by Sawyer and co-workers (1997b), Bunn (1994), and Mountain (1986) because of the 50% failure rate with surgery alone, no randomized studies have convincingly demonstrated that adjuvant treatments in these relatively early stages have an impact on survival. It is always a personal decision between a patient and his or her physicians as to whether any potential benefits of postoperative adjuvant therapies outweigh their risks and inconvenience. It is safe to say, however, that most physicians do not and should not currently recommend adjuvant chemotherapy in stage I and II NSCLC.
A locoregional intrathoracic failure rate of 31% was observed by the Ludwig Lung Cancer Study Group (1987) for completely resected stage II patients. Given the demonstrated success of radiation therapy as a modality for local control in medically inoperable early-stage patients, it has been a natural extension to think that postoperative adjuvant radiation might reduce the local failure rate. This has in fact been borne out in a number of studies. However, the reduction in the local recurrence rate with postoperative adjuvant radiation has not, unfortunately, translated into an improvement in survival in randomized studies. Thus, postoperative adjuvant radiation is also not generally recommended in stages I and II NSCLC.
Whether patients with stage IIIA disease discovered at the time of thoracotomy, who have not received neoadjuvant treatment, should receive postoperative adjuvant radiation or chemotherapy or both is more controversial.
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Although even in this advanced stage no randomized study that has been considered free of study flaws has documented improved survival with postoperative adjuvant treatments added to surgery alone, there is sufficient suggestive randomized and nonrandomized data to lead many physicians to carefully consider these adjuvant therapies in patients at such a high risk of recurrence, as noted by Lee and Ginsberg (1997) and Lilenbaum and Green (1994).
The former international staging system created by a collaboration of the American Joint Committee on Cancer Staging and the International Union Against Cancer, as reported by Mountain (1986), divided stage III lung cancer into two distinct groups. Stage IIIA comprised those lesions that are potentially resectable and included any N2 disease, any T3 primary tumors, or both. Stage IIIB designated those patients with disease that involves structures that usually preclude resection by a unilateral approach. These included T4 primary tumors and N3 nodal disease. The international staging system published in 1997 by Mountain has changed the categories in IIIA disease (see Chapter 98). However, most of the studies quoted in this chapter have used the former international staging system, and thus this system, albeit outdated, is used for the most part throughout this chapter.
Patients with T3N0 disease, which usually denotes chest wall invasion, are considered stage IIb in the revised classification published by Mountain (1997) because their survival is significantly better than patients who have been classified stage IIIA by virtue of N2 disease. Martini and Flehinger (1987) reported that 5-year survival in the former group approximates 60%. Thus, many have not considered this to be a group in whom adjuvant therapies are likely to be of great benefit.
According to Bulzebruck and co-workers (1992), approximately 20% of patients with NSCLC present with stage IIIA disease at diagnosis, and another 20% are stage IIIB at presentation. The overall median and 5-year survival for stage IIIA disease are 12 months and 15% to 20%, respectively, and for stage IIIB, 8 months and 0% to 5% as documented by Saijo (1998) and Yoshino and associates (1997). Results this poor with disease that is at least potentially resectable have made patients in stage IIIA (in particular N2) a focus for multimodality therapies.
Until recently, patients who presented with even ipsilateral involvement of mediastinal lymph nodes (N2) were considered inoperable and tended to be treated with radiation or chemotherapy alone. This therapeutic nihilism evolved because of the miserable survival and cure rates for this stage, as just noted. Collective results of operation alone for N2 disease demonstrate 5-year survival rates ranging from 14% to 30%, as recorded by Ginsberg (1993) and van Klaveren and co-workers (1993). Using mediastinoscopy, and possibly with further refinements positron emission tomography (PET), mediastinal lymph node involvement may be detected before thoracotomy, allowing the patient with N2 disease to be selectively treated with combination therapy in a neoadjuvant fashion, before resection. A number of investigators, including Vansteenkiste (1998), Sonett (1999), and Bueno (2000) and their co-workers as well as Rusch (1996), have looked at such neoadjuvant therapy for stage IIIA disease, and several small randomized trials of this approach have shown dramatic improvements in survival. In many centers, this approach has become the standard care for patients with limited (usually defined as less than multistation and nonextranodal) N2 disease. An important trial in this field is the currently maturing Intergroup Trial 0139, which will determine in randomized fashion whether surgery added to neoadjuvant chemoradiation has added benefit to chemoradiation alone.
Although patients with IIIB (N3) disease would at first glance appear to be unlikely to benefit from combined modality therapies including surgery, since N3 lymph nodes are out of the field of an ipsilateral mediastinal lymphadenectomy, several studies have suggested that neoadjuvant treatment followed by surgery for IIIB (N3) disease may also be of benefit.
Perhaps more theoretically appealing is the potential benefit of neoadjuvant treatment for IIIB (T4) NSCLC. Here the possibility of rendering a large, invasive tumor, which is unlikely to be resected with clean margins, resectable by first treating with chemotherapy, radiation, or both has obvious appeal. Nonrandomized studies have suggested that this approach may be effective, and it is an approach that has been adopted by many surgeons in fit patients who can withstand an aggressive treatment plan.
To summarize, then, multimodality treatment of NSCLC is most often currently considered in patients with disease that is stage IIIA or greater. The available evidence suggests that neoadjuvant treatment is more advantageous than postoperative adjuvant treatment, thus placing a premium on preresectional evaluation of mediastinal lymph nodes by mediastinoscopy. There is no strong consensus on the value of postoperative adjuvant treatment even in stages IIIA and beyond, but it is not unreasonable to consider this in generally healthy patients, preferably within a research protocol. The positive experience with neoadjuvant treatment in locally advanced cases has led some to suggest that similar benefits may be seen by applying neoadjuvant treatment to earlier-stage disease. Trials investigating this concept are ongoing.
Interpretations of the results of clinical trials in the field of combined-modality therapy must be carried out with great care. Many of the trials evaluating the aforementioned treatment regimens involved patients with bulky N2 disease but also included other patients with locally advanced disease, such as disease involving the chest wall (T3) or locally invading the mediastinum. Including patients with T3N0 chest wall disease would tend to improve overall survival in a trial because these patients, as a rule, have a better long-term outlook than patients with N2 disease, and these now
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are staged as IIB. Other trials included patients with stage IIIB disease (T4 primary tumor, contralateral mediastinal lymph nodes). Importantly, not all trials included rigorous staging of the mediastinum in the form of a mediastinal lymph node dissection.
A variety of therapeutic modalities have been compiled in review articles. One review by Brundage and Mackillop (1996) examined 441 phase II studies and 108 phase III reports that enrolled stage III patients between 1966 and 1993. Review of the literature demonstrated significant diversity in research practices. Analysis of trials for stage III management found five major types of variation between studies: selection of control arms, selection of study investigational arms, choice of eligibility criteria, outcomes measures selected for study, and magnitude of benefit sought in the primary outcome measure. This diversity of research studies has made it increasingly difficult to definitively decide what is the best treatment option.
As studies are reviewed, what parameters are truly reflective of clinical benefit to the patients should be considered. Median survival is not a particularly useful indicator. The aim as clinicians is to increase the number of long-term survivors. Also, another parameter to consider is response to induction therapy and adjuvant therapy. Grading of response, according to Milano and colleagues (1996), is a valid parameter to evaluate standard regimens and novel drug associations. Repeat mediastinoscopy after induction therapy also has been suggested by Pauwels (1998) and Olsen (1997) and their associates for restaging of the extent of the disease after the initial therapy.
ADJUVANT THERAPY
Adjuvant therapy refers to postoperative treatment, usually specific for chemotherapy, radiation therapy, immunotherapy, or some combination of these. Adjuvant therapy is aimed at those patients deemed to be at increased risk of local or distant relapse after surgical resection.
Adjuvant therapy was first used in the 1970s. Physicians were optimistic that cure was forthcoming because adjuvant therapy was able to stop NSCLC recurrences in animal models. Until the mid-1980s, however, analysis of various adjuvant therapies was difficult because of the differences in staging across various trials. In the early 1980s, with the advent of computed tomography (CT) and advances in imaging techniques, patients began to be more accurately classified and treated, and results recorded. Since then, initial optimism has been tempered by the demonstration of only modest improvement in survival rates, as discussed by Turrisi (1992). Currently, no convincing evidence exists that patients who have undergone complete surgical resection benefit in a significant way from postoperative treatment. For example, no postoperative adjuvant therapy regimen exists that has been definitively shown to prolong survival, as noted by Livingston (1997) and Johnson (1997) and their co-workers.
The first advance in structured adjuvant therapy came in the late 1970s and early 1980s. McKneally and colleagues (1976a, 1976b) compared a randomized group of 39 patients with resected stage I NSCLC who received 107 viable units of the Tice strain of bacillus Calmette-Gu rin (BCG) to those who received no further treatment. BCG treatment prolonged survival and time to recurrence in these patients. McKneally and associates (1981), in a 4-year follow-up, reported that the recurrence rate in the control population was high, 62% at 3 years, whereas the recurrence rate was 33% at 3 years in the BCG-treated group. The National Institutes of Health funded a consortium of institutions, the Lung Cancer Study Group (LCSG), to verify the results of this trial and to investigate other treatment modalities in separate trials. The LCSG was a collaboration of thoracic surgeons, medical and radiation oncologists, and pathologists who conducted clinical trials based on rigorous standards of staging and follow-up, as outlined by Holmes (1994b) and Lad (1990). This group routinely and systematically required assessment of mediastinal lymph nodes and helped establish the revised international staging system for NSCLC. During the 12 years of its existence, before being disbanded in 1989, the LCSG focused its attention on those patients who had disease localized to the thorax that was potentially resectable, as reported by Lad (1990) and Holmes (1992). This group made significant advances in the multimodality management of NSCLC, eventually completing nine studies before being disbanded (Table 112-1).
Table 112-1. Lung Cancer Study Group Trials for Non Small-Cell Lung Cancer | ||||||||||||||||||||||||||||||||||||||||||||
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The first trial started by this group, LCSG 771, was a randomized double-blind comparison of postoperative intrapleural BCG with isoniazid versus saline solution with isoniazid. Between 1977 and 1980, 473 patients were enrolled and followed until 1990, as reported by Feld (1984) and Gail (1984) and their colleagues. No evidence existed of improved survival or time to recurrence among patients given BCG in the group's report published by Gail (1994). The only differences between McKneally and associates' (1976a) study and the LCSG 771 were that the LCSG required lymph node biopsies for pathologic staging, injected intrapleural saline solution in the control group, and used isoniazid placebo instead of isoniazid in the control group beginning 14 days after instillation. Review of the data surrounding these two studies demonstrates that positive results, ultimately found to be caused by chance, are not uncommon in small preliminary studies, further underscoring the need for larger confirmatory trials. This experience convincingly demonstrated to investigators the importance of well-conducted clinical trials.
Over the years since this trial, numerous other adjuvant chemotherapy and radiation therapy trials have been conducted by both single institutions with large experiences and by other oncology groups formed specifically to
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answer important questions in clinical oncology. These groups include the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), the Radiation Therapy Oncology Group (RTOG), the European Organization for Research and Treatment of Cancer (EORTC), the Cancer and Leukemia Group B (CALGB), the Non Small Cell Lung Cancer Collaborative Group in Britain (1995), the Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan, 1995), and most recently, the American College of Surgeons Oncology Group (ACOSOG). Many of the trials conducted by these groups are summarized subsequently to provide a historical perspective.
Adjuvant Radiation Therapy
As noted by Curran (1995), since the 1960s postoperative irradiation often has been used in the management of NSCLC (Table 112-2). It has been well demonstrated that radiation therapy is capable of sterilizing carcinoma of the lung at the primary site and the regional lymph nodes when the radiation dose reaches 50 to 64 Gy. However, no definitive study has demonstrated that this translates to improved survival. Theoretically, postoperative radiation therapy should be beneficial. Whereas surgery may fail at the margins of disease, radiation therapy fails centrally where hypoxic conditions exist. Some studies, such as those of Israel
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(1978), Van Houtte (1980), Choi (1990), and Bleehen (1994) and their co-workers, have been able to show there is a dose response relation. However, the lung's ability to tolerate adjuvant radiation therapy continues to be a major concern.
Table 112-2. Adjuvant Radiation Therapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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One of the earliest encouraging studies came from the San Diego Naval Hospital. Investigators reported 66 resected patients with (IIIa) N2 cancer who were treated with a radiation dose of 30 to 60 Gy radiation after surgery. Green and Kern (1978) and Green and associates (1975) reported that the 5-year survival of these patients approximated 35%; in contrast, only 3% of 30 unrandomized patients treated with surgery alone survived 5 years.
The EORTC conducted two prospective trials of postoperative radiation therapy. In the first trial, 230 of 392 patients with squamous cell carcinoma were evaluated, 88 of whom had regional lymph node metastases. Israel and co-workers (1978) reported the 3-year tumor-free survival rate was 70% in 104 patients given postresection radiation therapy, compared with 50% in 126 treated with resection without postoperative irradiation. However, this result has been interpreted with caution because of the large and unbalanced numbers of patients excluded.
In the second EORTC trial, Van Houtte and colleagues (1980) in Brussels, Belgium, studied 224 patients without lymph node involvement (T1, T2, or T3 for main-stem bronchus involvement) and with complete resection of tumor. This trial included 14 patients with small cell lung cancer and two with pulmonary sarcoma. A postoperative radiation dose of 60 Gy in 6 weeks decreased the number of locoregional recurrences within the treatment field from 13% to 8%. In an analysis of 175 of 224 patients without evidence of lymph node metastases, 5-year survival was better in the nonirradiated group (45% vs. 24%). Although the survival difference was not statistically significant, the results suggested that adjuvant mediastinal radiation therapy may be harmful in patients with N0 or N1 disease.
In 1986, the LCSG reported on 230 completely resected patients with stage II and III squamous cell lung carcinoma treated between 1978 and 1985 (LCSG 773). A dose of 50 Gy was delivered over 5 weeks to 110 randomized patients. The locoregional failure rate was reduced from 41% to 3% with irradiation for all node-positive patients. In the control (no treatment) group (n = 108), 21 (19%) developed a first recurrence at a local site. Conversely, the radiation therapy group (n = 102) had only 1 (1%) local recurrence at the first site of disease (P < 0.001). However, as noted by Weisenburger (1994), the increase in locoregional control with irradiation did not translate into a survival benefit for stage II patients because more than two-thirds of the failures were secondary to distant metastasis. The LCSG did not separate patients with N1 and N2 disease. A similar trial, as documented by Curran (1995), was conducted by the EORTC (EORTC 08861) and was closed with incomplete accrual in 1992.
This study has been criticized by radiation oncologists such as Choi (1991) for using a radiation dose that many thought was too low. The study also did not contain a sufficient number of patients with mediastinal lymph node disease (N2) to detect a survival difference with any power. It has also been suggested by Cox (1991) and Choi (1991) that only 76% of the patients received within 5% of the dose, and the study included 12 control patients who received radiation therapy after having local recurrence without distant metastases. However, follow-up subset analysis of the survival of those patients who received within 5% of the protocol dose compared with those control patients who did not receive initial or delayed radiation therapy revealed no significant benefit in survival.
Bleehen and associates (1994), on behalf of the British Medical Research Council, reported on 308 patients with T1 2, N1 2 NSCLC. A dose of 40 Gy was delivered in 3 weeks to 308 patients. One hundred thirty-six patients received their complete course of postoperative irradiation. The median survival was 19 months in the surgery-alone group versus 17.5 months in the surgery and radiation therapy arm. The 1-, 3-, and 5-year survival rates were 68%, 16%, and 5%, respectively, for the surgery-only arm versus 61%, 21%, and 6% for the combined-modality group. Stephens and colleagues (1996) concluded that this trial provided no convincing evidence that postoperative radiation therapy affects survival, local recurrence, or development of metastases.
The randomized trials, then, have for the most part demonstrated decreased locoregional recurrence; however, this has not translated to any significant survival advantage. Other trials have demonstrated potential advantages of irradiation in selected subsets of patients. In patients with advanced disease (T3 4 or N2 3) or positive resection margins, radiation therapy almost certainly reduces local relapse. Some believe it may have further benefit in these subsets.
Kirsh and Sloan (1982) reported that at the University of Michigan, mediastinal lymph node dissection in conjunction with pulmonary resection was performed on 690 patients with bronchial carcinoma from 1959 through 1975. One hundred thirty-six of these patients had mediastinal lymph node metastases found at resection. One hundred ten patients who survived operation were treated with 50 to 60 Gy of postoperative irradiation. Of the patients who underwent irradiation, 18 (36%) of the 50 patients with squamous cell carcinoma survived 5 years, whereas only 7 (13%) of 55 with adenocarcinoma survived 5 years. In addition to demonstrating better local control by radiation therapy, this study suggested that histologic cell type in patients with mediastinal metastases is an important factor in prognosis.
From 1977 to 1980 at Memorial Sloan-Kettering Cancer Center, Hilaris and associates (1985) reported on 318 patients with stage III disease who underwent thoracotomy. After resection, all patients received external beam irradiation consisting of 30 to 40 Gy given over 2 to 4 weeks. One hundred of these patients were treated with intraoperative
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brachytherapy, the criteria for this being either the presence of residual gross disease or close resection margins. The local control in those patients with gross residual disease treated with brachytherapy and postoperative external beam irradiation was 72%. The overall 5-year survival was 22%. The 5-year survival was better in patients who had all gross disease removed than in patients who had gross residual disease (30% vs. 13%). The disease-free survival in these two groups was 27% and 12%, respectively.
At the Radiation Oncology Center at Washington University, St. Louis, Emami and colleagues (1987) reported on 173 patients with stages I (with positive margins), II, and III NSCLC who were treated with surgery and postoperative radiation therapy between 1974 and 1989. All patients were retrospectively reviewed and restaged according to the 1986 American Joint Committee staging classification. All patients were treated with a continuous course of radiation therapy with conventional fractionation of 180 to 200 cGy per day, the average receiving between 50 and 60 Gy over the course of their therapy. Seventy-four patients were stage IIIA and two were stage IIIB. Locoregional control for stages I, II, and IIIA was 85%, 75%, and 85%, respectively. Five-year actuarial survival was 35% for stage I with positive margins, and only 20% for stages II and IIIA. In a follow-up report, Emami and associates (1997) noted that patients with N0 disease but positive margins had a similar 5-year survival (25%) to patients with N1 and N2 disease (20%).
In a report from Barcelona by Astudillo and Conill (1990), 146 patients with pathologic stage IIIA NSCLC were retrospectively analyzed to determine whether postoperative radiation therapy (45 to 50 Gy) improved survival and reduced locoregional recurrences. The survival rates of the untreated group (n = 60) at 3 and 5 years were 28% and 12%, respectively. The 3- and 5-year survival rates in the radiated arm (n = 86) were 20% and 19%, respectively, failing to show any statistically significant differences. Patients with N0 and N1 disease were grouped, and survival at 3 and 5 years was 41% and 27%, respectively; for the T3N0 1 group, 17% and 15%, respectively; and for the T3N2 group, the survival was significantly worse. Median survival was 6 months for patients without irradiation and 15 months for those with irradiation (P = 0.071). A slightly decreased incidence of locoregional recurrence was observed in the group receiving postoperative radiation therapy.
A recent study from the University Medical School of Graz, Austria, reported by Mayer and associates (1997), randomized 155 stage I, II, and III patients to adjuvant radiation therapy of 50 to 56 Gy (n = 83) or no treatment (n = 72). The overall 5-year survival was 29.7% for the irradiated group and 20.4% for the control group (P 0.05, not significant). The rate of local recurrence was significantly smaller in the irradiated group, but once again, although local disease was better controlled, no survival advantage was demonstrated.
A retrospective review by Sawyer and co-workers (1997b) performed at the Mayo Clinic is perhaps the study most often cited by advocates of postoperative radiation therapy for patients with N2 disease. This study set out to determine the local recurrence and survival rates for 124 patients with N2 disease undergoing complete surgical resection with or without adjuvant radiation therapy. Although it is retrospective, the strength of this study lies in the pure cohort of N2 patients who were rigorously identified, as more than one mediastinal lymph node station was dissected in 98% of patients. Eighty-eight patients received adjuvant radiation therapy (range, 45 to 55 Gy; median, 50.6 Gy). After treatment with surgery alone, the 4-year local recurrence rate was 60%, compared with 17% for those with adjuvant radiation therapy (P < 0.0001). The 4-year survival rate was 22% for treatment with surgery alone in these N2 patients, compared with 43% for treatment with adjuvant radiation therapy (P = 0.005). On multivariate analysis, the addition of thoracic irradiation was associated with an improved survival rate.
The oft-cited PORT Meta-analysis Trialists Group study (1998) looked at individual patient data from nine randomized trials (2,128 patients) of postoperative radiation therapy versus surgery alone. The mean follow-up was 3.9 years for the survivors, and the results actually showed a significant adverse effect of postoperative radiation therapy on survival, with a 21% relative increase in the risk of death. This adverse effect was greatest in patients with stage I/II, N0 or N1 disease. For those with N2 disease no clear evidence of adverse effect existed. The group concluded that postoperative radiation therapy should not be used routinely in patients with early-stage disease and that its role in patients with N2 disease remains unclear. This study is somewhat misleading because few patients with N0 disease are irradiated routinely, and some selection factors must have been operable. Further, any meta-analysis is only as good as the data on which it draws, and the quality of several of the studies included in the analysis is questionable. A reasonable interpretation of this study that would be consistent with the findings of the majority of other studies of adjuvant radiation is that this therapy is at best of no benefit for completely resected N0 and N1 disease.
As noted by Stewart and Burdett (1997), we have seen that in patients with early-stage tumor without positive lymph nodes, few clinical trials (randomized or otherwise) have demonstrated any survival advantage when postoperative radiation therapy is given. In patients with advanced (N2) disease, however, Sawyer and colleagues (1997b) found in a carefully performed, but uncontrolled, retrospective study that postoperative radiation therapy has both local control and survival benefit. In prospective, randomized studies, however, improvement in locoregional control with radiation therapy has not translated into improved long-term survival; however, no such randomized study has looked specifically at patients with N2 disease as a subset.
All of these trials have been plagued with problems related to interpretation caused by heterogeneity of stage and inability to make conclusions based on each stage. The
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imaging methods used for determining local control are far from precise, and various studies have used different means to make this assessment. Differentiating scar from active tumor can be problematic. The use of positron emission tomography has the potential to improve the ability to distinguish active tumor from scar tissue. The fact that many of these studies were retrospective introduces the variable of selectivity into the equation: Why were certain patients selected for postoperative radiation therapy? Were they the worst patients who were not expected to do well and thus were given radiation therapy as attempted salvage after an incomplete surgical resection and staging, or were they patients with a better prognosis in whom radiation therapy was used as icing on the cake? Even prospective randomized trials must be looked at with caution, especially if it is not known how many patients were excluded from the study or chose not to participate.
Adjuvant Chemotherapy
The role of adjuvant chemotherapy in NSCLC remains as controversial as the role of adjuvant radiation reviewed in the preceding section. This uncertainty persists despite more than 30 years of research involving more than 10,000 patients in more than 50 randomized clinical trials, reviewed elsewhere by Bunn (1994), Marangolo and Fiorentini (1988), and Kris (1987) and Haraf (1992) and their colleagues. Theoretically, postoperative adjuvant chemotherapy is an attractive concept because this should be a time of minimal tumor burden. Adjuvant chemotherapy has been demonstrated to show a minimum increase in the disease-free interval after surgical resection in a number of other epithelial malignancies. Preclinical studies by Schabel (1977) in mice have demonstrated that surgical adjuvant chemotherapy for lung cancer increases the long-term cure rate and significantly increases the lifespan of treatment failures.
Two phases of adjuvant chemotherapy have occurred since the 1950s. In the 1960s and 1970s, trials of various drugs, chiefly alkylating agents, were highly ineffective. Not until the early 1980s, particularly from the experience of the LCSG, did the use of platinum-based chemotherapy usher in more effective management of NSCLC. Current evidence suggests platinum-based agents may be the most effective single drugs for the management of NSCLC patients, although newer agents such as paclitaxel, gemcitabine, irinotecan, and vinorelbine (Navelbine) all show significant activity. Now the more active combinations include cisplatin and can produce a response rate between 20% and 60%, although responses are higher in previously untreated patients given higher doses, as noted by the NSCLC Collaborative Group in Britain (1995), the Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan, 1995), and the trials reported by Cullen (1995a, 1995b).
Saijo (1998), in discussing new chemotherapeutic agents, raises the fundamental question of whether combination chemotherapy makes a difference, which remains to be seen. A meta-analysis demonstrated that combination chemotherapy increases survival at 3, 6, and 9 months, but not at 12 months. For the Eastern Cooperative Oncology Group trials, according to Bonomi (1998) and Natale (1998), two-drug combinations of platinum agents with a vinca alkaloid or etoposide provided the best overall survival with acceptable toxicity; more recent combinations combining platinum agents with taxanes have had similar effectiveness. Before taxanes, combination cisplatin and etoposide produced the highest 1-year survival rates when compared with several combined chemotherapy regimens (25% vs. less than 19%) and served as the group's standard reference regimen until 1997. It has not yet been clearly established whether regimens with cisplatin at doses of approximately 100 to 120 mg/m2 are more effective than regimens with a lower dosage of 50 to 60 mg/m2. Trodella (1997) and Paccagnella (1996) and their associates point out that it appears that combinations higher than 100 to 120 mg/m2 cannot further increase the response rate.
The third generation of chemotherapeutic agents for NSCLC has recently arrived, namely, paclitaxel and paclitaxel-based combinations. It is clear from multiple phase I and II studies that these agents have significant activity against NSCLC with acceptable toxicity. Information regarding the effectiveness of these and many other single agents (e.g., docetaxel, irinotecan, gemcitabine, and topotecan) and combinations from phase III studies is only very recently becoming available as trials mature.
Until fairly recently, NSCLC has been regarded as a chemoresistant tumor, mainly on the basis that the older established drugs (i.e., doxorubicin, methotrexate, cyclophosphamide) are ineffective. As noted by Cullen (1995a, 1995b), only five drugs (ifosfamide, mitomycin, cisplatin, vinblastine, and vindesine), when tested as single agents on large numbers of patients, produce major responses in 15% or more of cases. One could now add the taxanes, gemcitabine, and the tecans to this list. Two of the most frequently used drug regimens in the management of NSCLC have traditionally been mitomycin C, vindesine or vinblastine, and cisplatin (MVP) and cyclophosphamide, doxorubicin, and cisplatin (CAP). The MVP combination originally was developed by Gralla (1990) at Memorial Sloan-Kettering Cancer Center. According to Bonomi (1998) and Spain (1993), this regimen can produce a response rate of between 20% and 75%. The activity of mitomycin in NSCLC has been well documented, as noted by Spain (1993), in both single-institution pilot and multiinstitution randomized trials. Mitomycin is associated with excessive pulmonary toxicity, however, making the thoracic surgeon reluctant to use mitomycin-based regimens. The CAP regimen avoids the pulmonary toxicity of mitomycin but has a lower overall response rate.
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Clinical trials with adjuvant chemotherapy before the 1980s were plagued by many shortcomings in methodology. Often, the trials failed to differentiate between small cell cancer and NSCLC. Nodal status was rarely assessed, and clinical staging was inadequate before CT scanning was widely available. Only a limited number of trials were randomized or properly designed during this period.
The earliest and largest randomized, controlled postoperative lung cancer trial was started in 1957 by the Veterans Administration (VA) Surgical Adjuvant Lung Cancer Chemotherapy Cooperative Group, which involved 22 hospitals. In this trial, reported by Hughes and Higgins (1962), 1,002 patients were randomized to receive either intrapleural saline or nitrogen mustard immediately postoperatively on day 1 and on postoperative day 2. This trial failed to show any survival advantage over the control group. In a similar trial by the same group, 1,008 patients were randomized to receive placebo or short-term intravenous cyclophosphamide. Although there was less toxicity, the report by Higgins and coinvestigators (1969) also failed to demonstrate any survival advantage.
Slack (1970) reported the experience of the University Surgical Adjuvant Lung Project, which randomized 1,192 patients to receive placebo or nitrogen mustard, 0.4 mg/kg intrapleurally and intravenously, in the same manner as the VA experience. This study also failed to demonstrate any survival advantage. Postoperative complications were frequent in the control series (33%) but were significantly higher (45%) in the treatment series. There was 14% perioperative mortality.
The last large studies of the 1970s were those reported by Shields and colleagues (1974, 1977) conducted by the Veterans Administration Surgical Adjuvant Group. In one trial, 909 patients were randomized to receive either placebo or cyclophosphamide, 6 mg/kg intrapleurally postoperatively, followed by 4 days of intravenous treatment, and concluded with 8 mg/kg intravenously for 5 days during the fifth postoperative week. Again, there was no survival advantage associated with this approach.
Numerous other prospective randomized trials were undertaken to evaluate single-drug chemotherapy after resection of bronchogenic carcinoma, which often included small cell lung cancers. The drugs studied included mechlorethamine, cyclophosphamide, and methotrexate. In one of the largest of these studies reported by Shields and associates (1982), 865 patients were assigned to lomustine (CCNU) and hydroxyurea (n = 432) or no treatment. In all, a total of 2,348 complete resections were carried out; 1,172 patients received adjuvant therapy after the resection, and 1,176 underwent operation alone. The accumulated 5- and 10-year survival rates were 24.8% and 13.5%, respectively, for the treatment group and 26.2% and 16.3% for the control group. The differences were not significant. These survival figures further underscore the primitive nature of knowledge of staging in the early years of clinical trials.
The British Medical Research Council reported a long follow-up series in NSCLC, one in 1971 and one in 1985. The first report described 735 patients with bronchial carcinoma admitted between 1966 and 1968 who were treated postoperatively with long-term busulphan, oral cyclophosphamide, or placebo. The 2-year survival rate was 49% for busulphan, 50% for the cyclophosphamide arm, and 50% for the placebo arm. No statistically significant differences in survival existed. The 15-year follow-up reported by Girling and coinvestigators (1985) revealed 8% alive of the 243 allocated to busulphan, 9% in the cyclophosphamide group, and 10% of the 249 who received placebo.
By the mid-1980s, two advances had changed the direction of adjuvant chemotherapy: the introduction of the 1986 staging system by Mountain and the use of platinum-based agents. Some of the first postoperative platinum-based adjuvant chemotherapy trials were conducted by the LCSG, as reported by Holmes (1989). Study 772 reported by Holmes (1986) and Holmes and Gail (1986) included 141 patients with resected stage II (T2N1) and stage III (any T3 or N2) adenocarcinoma and large cell undifferentiated carcinoma randomized to receive either immunotherapy with BCG/levamisole or CAP once a month for 6 months. All patients underwent a prescribed, rigorous, intraoperative lymph node staging procedure. At a median follow-up of 7.5 years, the median time to recurrence was 15 months for the chemotherapy group, compared with 8 months for the immunotherapy arm (P = 0.032). The median survival was 23 months for the chemotherapy group compared with 16 months for the immunotherapy group (P = 0.113), and the survival at 2 years was 42% for the chemotherapy group versus 32% for the immunotherapy group. Holmes (1993) pointed out that if one excludes the 15 patients in the treatment group who did not receive the CAP therapy, the improvements become even more statistically significant: P = 0.005 and P = 0.013, respectively. The main criticism of this trial was the lack of an adequate control. However, as noted by Holmes (1994a), the LCSG was reluctant to use a no-treatment arm in these patients in view of their perceived poor prognosis after surgery. This study suggested that CAP chemotherapy might have an effect on disease-free survival and death from cancer in patients with advanced, resectable NSCLC. This trial provided the impetus for a number of later clinical trials.
LCSG study 801, reported by Feld and colleagues (1993), consisted of 269 stage I and II (T1N1 and T2N0) patients who were randomized to receive four cycles of CAP chemotherapy administered every 3 weeks starting within 1 month of surgery. The dose of cisplatin was 60 mg/m2, significantly higher than LCSG trial 772; however, as noted by Feld and associates (1994), only 53% of patients received all four cycles and only 57% of those treatments were administered at the prescribed time. There were 101 recurrences, most of which were extrathoracic. No difference in time to recurrence or overall survival occurred
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between the treatment group and the no-treatment control arm even when the analysis was adjusted for specific prognostic variables. The LCSG investigators concluded that better systemic therapy was needed for completely resected early-stage patients.
The LCSG 853 study, reported by Figlin and Piantadosi (1994), randomly assigned 188 patients with completely resected stage II (41%) and stage III (59%) NSCLC to receive either immediate or delayed CAP chemotherapy administered at the time of first systemic relapse. Both the median time to recurrence and overall survival did not differ significantly between the two groups.
Niiranen and colleagues (1992) subsequently reported a randomized CAP regimen from the Helsinki University Central Hospital in which CAP was given monthly for six cycles to a group of 110 patients with any N0 tumor. Five-year survival was 67% versus 56% in controls, 10-year survival was 61% versus 48%, and recurrence rate was 48% versus 31%. The investigators concluded that patients with NSCLC of pathologic stage I who undergo radical surgery benefit from adjuvant chemotherapy. Of note, patients in the chemotherapy arm who completed six cycles had a slightly better 5-year survival than those who discontinued (72.5% vs. 50.3%, P = 0.15). However, this study has been criticized because of a disparity in the distribution of prognostically important clinical characteristics between the two arms despite the randomization.
The Japanese have also contributed significantly to the knowledge regarding adjuvant chemotherapy for NSCLC. Ohta and colleagues (1993), reporting for the Japan Clinical Oncology Group, reported on 209 patients with completely resected stage III NSCLC who were randomized to receive postoperative cisplatin and vindesine chemotherapy or no further treatment. No statistically significant difference existed in disease-free and overall survival between the chemotherapy (n = 90) and control (n = 91) arms. In the chemotherapy group, the median survival time and the 3- and 5-year survival rates were 31 months and 48% and 35%, respectively. Those of the control group were 37 months and 51% and 41%, respectively.
The Study Group of Adjuvant Chemotherapy for Lung Cancer in Chubu, Japan (1995), randomized 333 stage I, II, and III NSCLC patients to either adjuvant cisplatin, doxorubicin (Adriamycin), and uracil-FT (n = 155) or surgery only (n = 154). The 5-year survival in the therapy group was 61.8% versus 58.1% in the no-adjuvant-treatment arm. No statistically significant difference existed in the survival between these two groups (P 0.2).
An encouraging series of trials from the West Japan Study Group for Lung Cancer Surgery has been reported in the past several years, evaluating the orally administered drugs tegafur and uracil. The first such study was from Wada and colleagues (1996) and examined patients with all stages of NSCLC, allocating 323 patients into one of three different treatment arms: surgical resection alone, resection followed by three courses of cisplatin and vindesine with 1 year of oral tegafur and uracil, or resection followed by 1 year of oral uracil. Uracil inhibits 5-fluorouracil degradation and has antitumor activity as well. Wada and coinvestigators (1997) noted that 5-year follow-up was completed successfully on all patients and that there was good compliance and acceptable toxicity. Both chemotherapy treatment groups had improved 5-year survival (60.6% for oral tegafur and uracil, P = 0.08; 64.1% for uracil, P = 0.02) as compared with the surgery-alone groups (49.0%). Most of the patients had stage I disease, and another 36 had stage III disease. However, only 62 (20%) of the 310 patients in this study had locally advanced disease (stages IIIA, IIIB); the results of this subset were not presented individually, and thus the usefulness of this adjuvant regimen for locally advanced lesions remains unclear.
A subsequent randomized, controlled trial for patients in stages I and II reported by Wada and collaborators (1999) enrolled 229 patients to either surgery alone or surgery followed by cisplatin/vindesine/mitomycin and uracil plus tegafur for 1 year. Overall 5-year survival was not statistically different between the groups (71.1% vs. 76.8%). However, subgroup analysis showed that T1N0 patients had a benefit in the chemotherapy arm (P < 0.05), with a 5-year survival rate of 90.7% vs. 75.3%. This is certainly not a dramatic effect, and interestingly it appears to be most pronounced in early-stage disease, but nevertheless a small effect has been identified.
Similarly, a very small but significant improvement has been found in an early-stage subset with a different drug in another Japanese study published by Kato and associates (2001). In this study, the immune modulator Ubinimex was evaluated in patients with completely resected stage I squamous cell carcinoma. Both 5-year and disease-free survival improved (81% vs. 74%, and 71% vs. 62%, respectively; P < 0.05). These data have only appeared in abstract form.
In conclusion, outside of these isolated Japanese trials, no group or subset of patients has been demonstrated to definitively benefit from postoperative chemotherapy (Table 112-3). The use of active single agents or combinations was tested early in the 1960s and the 1970s. The observation that these were ineffective is not surprising in view of the relative inactivity of most of these chemotherapeutic agents in unresectable NSCLC. With the introduction of cisplatin-based regimens, considerable enthusiasm for postoperative adjuvant chemotherapy developed. Nevertheless, after all the years and all the trials, postoperative chemotherapy still should probably be confined to clinical trials, and little justification exists for its use outside of a protocol setting. It should be recalled that a full course of therapy can require 6 months, a period approximately equal to any possible survival benefit. If adjuvant chemotherapy is to be used outside of the trial setting, this would be most appropriate in healthy, younger patients with advanced disease those
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who are most likely to benefit and least likely to suffer important toxicities.
Table 112-3. Adjuvant Chemotherapy for Non Small-Cell Lung Cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Aside from the studied agents being ineffective, possible reasons for the failure of clinical trials to show reproducible benefit include an inadequate sample size to detect small survival benefits, as was required to establish the place of adjuvant therapy in breast cancer, and inadequate drug delivery.
Adjuvant Chemoradiation Therapy
Given the results obtained with adjuvant chemotherapy or radiation therapy separately, a number of investigators have tried using combined postoperative chemoradiation therapy to assess whether the combination might provide a greater benefit (Table 112-4). Use of chemotherapy and radiation therapy together potentially offers a number of advantages. Ideally, chemotherapeutic agents used simultaneously with radiation therapy should enhance the effects of radiation therapy on tumor without producing excessive toxicity. Using chemotherapy before radiation therapy allows the opportunity to give chemotherapeutic agents at full-dose intensity, whereas using radiation therapy before chemotherapy has the potential advantage of being able to use continuous thoracic irradiation at full dose. The optimal sequence for chemotherapy and radiation therapy in stage III NSCLC has not been determined.
Table 112-4. Adjuvant Chemoradiation Therapy for Non Small-Cell Lung Cancer | |||||||||||||||||||||||||||||||||||
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Lad (1994) reported the Lung Cancer Study Group trial 791, which was the first LCSG study to include all non small cell histologies in an adjuvant study. This study looked at 172 patients with incompletely resected tumors, as defined by the presence of residual tumor at the margins or the presence of metastatic tumor in the highest paratracheal
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lymph nodes sampled. The study randomized patients to postoperative radiation therapy (40 Gy) alone or radiation therapy with six cycles of cyclophosphamide (400 mg/m2) plus doxorubicin (40 mg/m2) plus cisplatin (40 mg/m2). No untreated control arm was used. Although only 51% of the patients completed the prescribed chemoradiation therapeutic regimen, the investigators showed some advantage for chemoradiation over radiation alone. Median survival in the chemoradiation therapeutic group was not significantly different at 20 months compared with 13 months (P = 0.13) with radiation therapy alone. However, median time to recurrence was 14 months and 8 months (P = 0.004), respectively. Recurrences were more common in the patients who had radiation therapy than in those given CAP plus radiation therapy and were usually extrathoracic (66 versus 50, P = 0.001). Simultaneous irradiation and chemotherapy were able to be delivered without untoward local toxic reactions.
At the University of Chicago, Ferguson and coinvestigators (1986) reported a nonrandomized, retrospective study of 34 patients with stage II disease. Patients were treated with resection alone or with resection followed by radiation therapy, chemotherapy, or both. Chemotherapy involved cyclophosphamide, doxorubicin, and methotrexate on days 1 to 8, followed by oral procarbazine on days 3 to 13. These cycles were repeated monthly for 1 year. Median survival in the chemoradiation therapy arm was increased to 45.5 months compared with 19.2 months in the radiation therapy group and 13 months in the control groups (P < 0.005). The 5-year survival rate in this group was 45.9%, compared with 28.6% in the radiation therapy only group. The investigators concluded that adjuvant radiation therapy and chemotherapy offered an improved median survival over resection alone in this special subset of patients with N1 tumor.
At Memorial Sloan-Kettering Cancer Center, a prospective randomized trial was performed to determine whether postoperative chemotherapy with vindesine and cisplatin could lengthen time to progression and overall survival in 72 patients with stage III disease. All had surgery and mediastinal irradiation for 6 to 7 weeks postthoracotomy. Incompletely resected patients had intraoperative iodine 125 implantation, iridium 192 implantation, or both. Vindesine and cisplatin were planned for the 36 patients randomized to additional chemotherapy. No difference in time to progression (median, 9.2 months for radiation therapy and chemotherapy vs. 9.0 months for radiation therapy alone, P = 0.35) or overall survival (16.3 months for radiation therapy and chemotherapy versus 19.1 months for radiation therapy alone, P = 0.42) was found by Pisters and associates (1994).
Compared with LCSG 772 and LCSG 791, this trial differed in that all patients had mediastinal lymph node involvement. In addition, the planned cisplatin dose intensity was roughly twice that of the other LCSG studies. Despite the differences among the three studies, Pisters and colleagues (1994) noted that if one examines the survival difference at 2 years between patients receiving postoperative cisplatin-based chemotherapy and controls, the 95% confidence intervals for the difference overlap. Although the authors concluded that an important survival advantage is not gained by adjuvant cisplatin chemotherapy, these results are difficult to assess because of the small numbers. The Memorial Sloan-Kettering experience had only 13 of 30 patients who received all four planned doses of cisplatin. LCSG 772 and LCSG 791 only looked at another 60 to 80 patients.
Currently, thoracic surgeons, medical oncologists, radiation oncologists, and pathologists have joined forces to determine the most effective management of NSCLC. Since the last LCSG 791 trial, an intergroup trial has been under way that calls on the collaborative efforts of the CALGB, ECOG, SWOG, RTOG, and the North Central Cancer Therapy Group. This Intergroup INT-0115 trial seeks to determine whether chemotherapy plus radiation therapy improves survival compared with radiation therapy alone in patients with completely resected stage II and IIIA NSCLC. CAP has been replaced by cisplatin and etoposide as a frontline cancer combination. Chemotherapy is administered beginning shortly after surgery and is continued for four courses. The target accrual was 462 patients, a number that has been reached. The study has been closed. We are not aware of publication of the final results, but a preliminary report by Rusch and Feins (1994) did not suggest a benefit for the chemoradiation therapy arm.
Of note in this large intergroup trial is the lack of a no-treatment arm despite the evidence that radiation therapy is of no benefit in prolonging survival. Despite the evidence, there remains a built-in bias that patients with stages II and IIIA disease should get some postoperative treatment, so the radiation therapy only arm is the control arm in this trial.
NEOADJUVANT THERAPY
In the early 1980s, neoadjuvant therapy, a term that implied treatment given before definitive surgical management, began to be used in the treatment of NSCLC. Previously, patients with bulky tumor or extensive nodal involvement usually were not considered surgical candidates and were treated with radiation therapy as definitive treatment.
With the introduction of the concept of neoadjuvant therapy, chemotherapy or radiation therapy or both began to be given to reduce bulky tumor or sterilize lymph nodes in an attempt to convert marginally unresectable or unresectable disease to resectable disease. As suggested by Shepherd (1993) and reemphasized by Green and Barkley (1997), preoperative or induction therapy theoretically may have advantages in being used before resistant clones of cells have the opportunity to develop. Also, treatment before resection allows the clinician to assess tumor responsiveness,
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helping to identify patients who may benefit from continuation of postoperative adjuvant chemotherapy. Finally, neoadjuvant therapy in concept might lessen the incidence of later distant disease when given at a time when only micrometastatic disease may be present.
A number of contrary positions exist regarding neoadjuvant therapy. Tumors might progress during the delay to the time of operation and a previously resectable tumor might become unresectable. Preoperative therapy is associated with systemic toxicity that might cause difficulty during the postoperative recuperation and wound healing. Several chemotherapeutic agents are associated with pulmonary toxicity and can result in reduced pulmonary function. Publications by Roberts (2001), Martin (2001), and Novoa (2001) and their associates, as well as by Torre and Sierra (2002), addressing the question of whether patients who have undergone neoadjuvant therapy are at increased risk of postoperative complications have had conflicting results. However, there is little doubt that following right pneumonectomy these patients are at high risk, and every effort should be made to avoid right pneumonectomy in these patients.
Resections after postoperative therapy can be extremely difficult and potentially hazardous because of the fibrosis that often results as a response to the therapy. Tissue planes may be obliterated because of mediastinal fibrosis. This is especially significant when there has been a response in the lymph nodes, because the nodes are intimately associated with the pulmonary artery and its branches, often making resection quite challenging. Because of this progressive fibrosis, patients are ideally taken to the operating room 3 to 5 weeks after the completion of induction therapy. It is particularly important to have proximal control of the pulmonary artery before undertaking a resection in a patient who has received preoperative therapy. Resections of this type ideally should be undertaken by a surgeon experienced in dealing with complex resections so as to avoid an unnecessary pneumonectomy.
Despite these possible difficulties associated with neoadjuvant treatment, reasonably strong evidence from small, randomized trials exists that neoadjuvant therapy results in improved survival when compared with surgery alone for stage IIIa (N2) disease. However, this has never been confirmed in the type of larger, multiinstitutional, phase III study that is likely to convince most in the field. Further, it is difficult to assess the various nonrandomized reports of neoadjuvant therapy. Staging criteria have differed widely, as have inclusion criteria. The criteria used to determine mediastinal lymph node involvement have varied from simple radiologic evidence to pathologic confirmation. The majority of studies do report a 50% to 60% objective response rate, although the complete response rate tends to be less than 15%. The overall response rate is significantly higher than when these same agents are used in patients with disseminated disease. In the reports of Blanke and Johnson (1995), Pujol and associates (1995), Holmes and Ruckdeschel (1994), and Shepherd (1993), the vast majority of responders to neoadjuvant chemotherapy and approximately one-half the patients overall are able to go on to surgical resection. Median survival is approximately 18 months for patients receiving combined-modality treatment including induction chemotherapy (ranging from 8 to 30 months), with 2- to 3-year survival ranging from 25% to 30%. Although it may seem that the median survival of approximately 18 months is superior to that of surgery or radiation therapy alone, one must remember that the patients in these trials represent a select subgroup of stage III patients overall, usually patients with the best performance status, and that this survival advantage may reflect patient selection rather than actual improvement with therapy.
Neoadjuvant Radiation Therapy
Neoadjuvant radiation therapy is at face value an appealing concept. Preoperative radiation has a good chance of reducing the tumor size, facilitating resection or possibly even downstaging the tumor. It may also minimize seeding of tumor cells by surgical manipulation and sterilize the tumor bed, but evidence for this is lacking. Faber (1994) has pointed out that tumor cells are particularly sensitive to radiation therapy at higher oxygen tensions; therefore, preoperative use would be expected to be most effective on the highly vascularized peripheral border of the invasive tumor. Depending on the total dose of radiation delivered preoperatively, investigators, including Reddy (1990), Sherman (1978), and Shields (1970) and their associates, as well as Warram (1975) and Bloedorn (1964), have reported a range of 20% to 50% of patients having no persistent tumor or only microscopic disease in the resected specimen. One of the problems with preoperative radiation therapy, however, is a tendency for significant fibrosis and loss of distinct tissue planes, making resection challenging. The doses required to obtain a response when given as a single agent, further, may be associated with decreased healing of the bronchial stump and resulting bronchopleural fistulae.
The first use of neoadjuvant radiation therapy dates back to 1955, when Bromley and Szur (1955) at the Hammersmith Hospital used a dose of 45 Gy before surgical resection (Table 112-5). Sixty-six of 573 patients were resected. At operation, no viable tumor was found in 47% of the patients. Ten of the patients died of complications within the first month, and only two patients were alive 5 years later. Subsequently in 1964, Bloedorn used a radiation dose of 60 Gy preoperatively to treat 109 patients with presumed unresectable lung cancer. The postoperative mortality was approximately 35%, and the 1-year survival approached 20%. Bloedorn (1964) reported that tumor sterilization rates of 54% at the primary site and 92% at the mediastinal lymph nodes were obtained, but the status of the mediastinal nodes was not histologically documented before initiation of the preoperative regimen. Thus, it was suggested that irradiation
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at 50 to 60 Gy is able in some cases to convert a surgical resection from incomplete to complete.
Table 112-5. Neoadjuvant Radiation Therapy for Non Small-Cell Lung Cancer | |||||||||||||||||||||||||||||||||||||||||||||||||
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Other phase II trials included the following: A report from the Harvard Medical School evaluated 53 patients with marginally resectable NSCLC treated with 30 to 40 Gy of preoperative radiation therapy followed by resection and postoperative radiation therapy. Thirty-eight (72%) patients were resected. Sherman and colleagues (1978) reported that the 5-year survival rate for the 38 resected patients was 27%, whereas it was 18% for all 53 patients. At Rush-Presbyterian-St. Luke's Medical Center, Reddy and associates (1990) reported on 74 patients with clinical stage III NSCLC who were treated with a 40-Gy preoperative radiation dose to the primary tumor in the lung and regional lymph node areas. Fifteen patients (20%) did not undergo operation because of tumor progression, patient refusal, or death. At the time of surgery, 2 patients had histologically negative specimens, 9 patients had microscopic disease only, and 37 patients had gross residual disease. The 5-year survival and recurrence-free survival rates for the entire group were 20% and 24%, respectively. Patients with a complete pathologic response had a recurrence-free survival rate of 53% at 5 years, whereas only 17% of those with gross residual disease at surgery remained recurrence free at 5 years. One-half of the patients with clinically uninvolved nodes were living recurrence free at 5 years, compared with only 20% of the patients with N2 disease.
In the 1960s and 1970s, the Veterans Administration and the National Cancer Institute performed two large-scale trials that randomized patients to immediate surgery versus preoperative 40- to 50-Gy radiation. In the Veterans Administration study reported by Shields and associates (1970), 331 male patients with biopsy-proven bronchial carcinoma were randomized. No statistically significant increase in survival was noted in the pretreatment group (12.5% vs. 21.0%). In fact, as noted by Shields (1972), the survival rate in the preoperative treatment group was significantly lower during the first 12 postoperative months than in those patients who only underwent resection.
In the National Cancer Institute study (1969), patients thought to be resectable at the time of diagnosis were randomly assigned to receive either immediate surgery (n = 278) or preoperative irradiation followed by surgery (n = 290). The 3-year survival rates for these two groups were nearly identical. At 5 years, Warram (1975) reported that the survival rate was 14% after preoperative radiation therapy and 16% after immediate surgery. The preoperative radiation therapy was believed not to improve the resectability or survival rates in either study. Long-term survival was not improved even though local control was enhanced. Operative mortality was 12% in both groups.
These trials certainly did not identify a benefit of neoadjuvant radiation therapy. However, since these trials lacked pretreatment histologic staging and there was significant variation in the amount of radiation therapy delivered and excessively long intervals between radiation therapy and surgery, the issue was not put completely to rest. Furthermore, some of the trials did not exclude patients with small cell histology.
By the late 1980s, an interesting phase II clinical trial was started by the LCSG to determine whether either preoperative radiation or chemotherapy was sufficiently active and safe to merit further work. Each arm was to be evaluated for its ability to induce an approximate 15% incidence of complete histologic clearance. Sixty-seven patients with stage III NSCLC were enrolled to receive either preoperative MVP chemotherapy (cisplatin, 120 mg/m2; mitomycin, 8 mg/m2; vinblastine, 4.5 mg/m2) or preoperative radiation therapy (44 Gy). All patients had systematic surgical staging of the mediastinum. Radiologic response to treatment was virtually identical for the two approaches (54% vs. 48%), with 29 of the 57 available patients achieving objective responses. Twenty-three (40%) of the 57 patients eventually underwent complete tumor resection. Wagner and associates (1994) recorded that median survival for the entire group was 12 months, with a 4-year survival rate of 27%. Thus, despite rigorous staging and excellent quality control, a more favorable stage III subset had a disappointing result.
Neoadjuvant Chemotherapy: Unrandomized Trials
Pastorino (1996), Cullen (1995b), Vokes (1990), and Kris and colleagues (1987) have shown that neoadjuvant chemotherapy also may offer benefits in the management of
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NSCLC. It has the potential of reducing tumor size, may prevent tumor progression caused by perioperative immunosuppression and release of growth factors related to wound healing, and theoretically may eliminate clinically occult micrometastases. As suggested by a mathematical model, chemotherapy can eradicate a neoplastic subclone if the number of cells is less than 106. Further, neoadjuvant chemotherapy gives the oncologist an opportunity to assess individual tumor sensitivity. The degree of response can be assessed histologically from the surgically resected specimen. From these results, Pujol and associates (1995) suggest that it may be possible to individualize postsurgical treatment.
Many investigators, including Tonato (1996), Shepherd (1993), Ginsberg (1993), and Ihde (1988), even before the publication of randomized trials on the issue, had taken the position that neoadjuvant chemotherapy is beneficial in patients with otherwise inoperable stage IIIA NSCLC. The long-term survival in phase II studies has reached 18%, compared with 9% of historic control subjects, as reported by Pastorino (1996). Although many centers have essentially adopted neoadjuvant chemotherapy as their standard management of stage IIIA (N2) NSCLC on the basis of these data and the available small phase III studies, many remain skeptical about neoadjuvant chemotherapy because of what they consider the weaknesses of these trials. Many of these studies have poorly defined eligibility criteria, poor pretreatment staging systems, or lack of adequate numbers to draw a definitive conclusion. However, efforts continue to define the role of neoadjuvant chemotherapy in the management of stage IIIA disease (Table 112-6).
Table 112-6. Neoadjuvant Chemotherapy for Non Small Cell Lung Cancer, Unrandomized Studies | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Perhaps the prototype phase II trial of neoadjuvant therapy was begun by investigators at Memorial Sloan-Kettering Cancer Center in 1986 and reported by Kris (1995) and Martini (1993) and their associates. A preliminary phase I/II clinical trial conducted between 1984 and 1986 on 41 patients with bulky N2 disease set the stage for this trial. The preliminary trial reported by Armstrong and co-workers (1992) demonstrated that a treatment program that consisted of induction chemotherapy, operation, and postoperative radiation therapy (reserved for patients with residual disease at thoracotomy) yielded acceptable and perhaps improved median survival and long-term survival for some patients. In the subsequent study, again trying to keep the patient population
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as homogeneous as possible, only patients with bulky N2 disease were entered. Patients received two to three cycles of mitomycin C, vindesine or vinblastine, and high-dose cisplatin (120 mg/m2). Four to six weeks later, they underwent surgery even if no radiologic response could be shown, as long as no progression of disease occurred. This experimental design, with a few variations, became the model for numerous other studies that followed, including those at the cooperative group level. A 77% major radiographic response rate to the chemotherapy occurred (105 of 136 patients), with a 10% (13 of 136) incidence of complete response. Of these patients, 98 had a thoracotomy. Complete resection was achieved in 65% of patients, and no histologic evidence of tumor was found in 19 (21.3%) completely resected patients. Median survival for the completely resected group was 27 months, with a 3- and 5-year survival rate of 44% and 26%, respectively. For the entire group, overall survival at 1, 3, and 5 years was 72%, 28%, and 17%, respectively. In patients in whom a pathologic complete response was achieved, survival was 95%, 71%, and 61% at 1, 3, and 5 years, respectively. Median survival was 64 months in this group. Also of note, 78 of 136 patients received postoperative radiation therapy to the mediastinum.
This trial, as reported by Kris (1995) and Martini (1993, 1997) and their associates, demonstrated that with a combined chemotherapy and surgery approach, survival in stage IIIA patients with the worst prognosis (those with bulky N2 disease) could approximate that observed in patients with the best prognosis (microscopic N2 disease discovered at the time of thoracotomy in a patient in whom it was not suspected). This represents a significant advance when one realizes that with surgery alone, essentially a 0% survival at 3 years exists in the group of patients with bulky mediastinal nodal disease and less than a 10% rate of resectability.
A number of other phase II trials conducted by Burkes (1992), Elias (1994), Skarin (1989), Kirn (1993), Pisters (1993), and Wagner (1994) and their colleagues using preoperative chemotherapy have essentially confirmed the previously mentioned results, but the optimal induction regimen has yet to be determined because of the heterogeneity of the patients entered in these trials. Among the various trials, the response rates to induction chemotherapy varied from 60% to 77%, and resectability rates ranged from 56% to 90%. The percentage of patients able to undergo complete resection ranged from 46% to 76%, and approximately 10% to 20% were found to have a pathologic complete response.
These various trials with MVP demonstrate the high major response and resectability rates. Concerns have remained, however, about the perceived risk of mitomycin-induced pulmonary toxicity, especially postoperative adult respiratory distress syndrome. An 11% mitomycin-associated pulmonary toxicity occurred in the Memorial Sloan-Kettering experience in patients who received a cumulative dose of 24 mg/m2.
The results obtained from CALGB protocol 8935, a multiinstitutional phase II trimodality study for stage IIIA disease reported by Kumar and coinvestigators (1996), are illustrative both from the standpoint of the magnitude of the therapy and the patterns of recurrent disease. This study enrolled only patients with N2 disease documented by mediastinoscopy, who subsequently received two cycles of preoperative chemotherapy consisting of cis-platinum, 100 mg/m2, and vinblastine, 5 mg/m2. Sugarbaker and associates (1995) emphasized that the surgery included resection of the primary tumor and a complete mediastinal lymph node dissection. Patients who could be completely resected received an additional two cycles of postoperative chemotherapy and 5,400 cGy of radiation therapy. Patients with unresectable disease received postoperative radiation therapy only, to a dose of 5,940 cGy.
Only 63 (85%) of 74 patients entered in the trial were able to complete the induction chemotherapy regimen as planned. Forty-six (73%, but only 62% of those originally enrolled in the trial) of the 63 patients underwent resection, of whom only 23 of these were complete resections, whereas 17 (27%) were unresectable. Thirty-three (72%, but only 44% of those originally enrolled in the study) of the 46 resected patients completed the postoperative chemotherapy and radiation therapy as planned. Overall survival at 3 years was 23% for all 74 eligible patients. Survival rates at 3 years for completely resected, incompletely resected, and unresectable patients were 46% (median, 20.9 months), 25% (median, 17.8 months), and 0% (median, 8.5 months), respectively. Of the resected patients, 28 experienced a recurrence, with all but one having distant disease.
These data demonstrate that trimodality therapy is a difficult regimen to complete even for patients in optimal shape with minimal or no weight loss. Granted, some of the patients progressed during the induction regimen, resulting in their failure to complete the protocol, but of those who underwent operation only approximately two-thirds completed the postoperative therapy. Distant failure remains the major limitation despite the intuitive notion that treating distant micrometastatic disease should be advantageous. The success in controlling local disease has not translated into prevention of distant disease, which likely is present early in the course of disease but only comes to attention later in the course. Again, this begs the question regarding the contribution toward long-term survival made by the operation over and above the selection factor.
At the University of Miami, an intensive multimodality therapy protocol incorporating neoadjuvant chemotherapy was initiated in July 1985 for patients with either borderline resectable or unresectable stage III NSCLC. All patients tolerated chemotherapy with 5-fluorouracil, etoposide, and cisplatin (PEF). The PEF combination appears to yield results similar to MVP. The advantages of PEF over MVP are a lower incidence of myelosuppression and the inclusion of two radiosensitizers, namely, cisplatin and 5-fluorouracil.
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Also, mitomycin, with its potential for pulmonary toxicity, is avoided in the PEF regimen. As reported by Sridhar and associates (1993), complete response to the induction regimen occurred in 2 patients (6%) and a partial response in 22 (63%). Thirty-two patients underwent surgery, and 26 patients were rendered disease free, including 2 found disease free at operation. The median survival for all patients was 19 months, with those undergoing incomplete surgical resection achieving 12 months and patients rendered disease free at operation achieving 21 months.
The Perugia group, as reported in 1988, enrolled 46 patients with clinical N2 disease and gave two to three cycles of neoadjuvant cisplatin and etoposide. Darwish and associates (1994) reported that the overall response rate was 37 (82%) of 45. Surgical exploration was carried out in 35 patients, with complete resections possible in 28 (62%) patients. Median survival for the entire group was 24.5 months, with a 2-year survival of 53%, similar to previously reported studies. However, unlike these studies, pathologic documentation of N2 involvement was not required in this trial, leaving some question regarding the true stage of disease in each patient.
Between September 1987 and September 1989, Pujol and colleagues (1990) enrolled 33 patients with T3N2M0 (n = 32) and T4N2 (n = 1) NSCLC in a phase II trial evaluating three cycles of preoperative etoposide, cisplatin, ifosfamide, and mesna for 4 days. Responding patients underwent thoracotomy and then received 45 Gy of thoracic irradiation. Chemotherapy induced a 55% partial response rate, and a 15% complete response rate and complete resection were achieved in 55% of patients. Complete response was histologically confirmed for five of the complete responders. Pujol and co-workers (1994, 1995) reported that the median survival was 11 months, although six patients were long-term survivors (3-year survival rate, 19%).
At the University of Navarra, Aristu and associates (1997) reported on 62 patients with histologically confirmed stage III NSCLC who were treated with neoadjuvant chemotherapy of cisplatin, mitomycin, and vindesine. Each cycle was repeated every 4 weeks for one to six cycles. Resection was attempted 4 to 5 weeks after the last course of chemotherapy. Intraoperative radiation therapy of 1,000 to 1,500 cGy was delivered, and postoperative external beam radiation therapy of 4,500 cGy was begun 4 weeks after surgery. Only partial responses were seen (64%), and 29 patients (53%) underwent resection. The median survival time was 10 months, and the 5-year survival rate was 29% and 7% for stage IIIA and stage IIIB, respectively. In spite of the similar response rates for stages IIIA and IIIB in this study, differences exist in complete resection (86% versus 40%) and in disease-free and local disease-free survival (50% to 70% versus 28% to 36%, P = 0.15 and 0.55, respectively).
At the University of Pisa, from 1990 to 1993, 36 patients were enrolled by Chella and colleagues (1995) in a phase II study aimed at determining the feasibility of surgery, patterns of disease recurrence, and survival after neoadjuvant and adjuvant MVP therapy in NSCLC. Cisplatin was administered at a dose of 90 mg/m2. The overall objective response was 78.1%. Three histologically complete responses and 22 partial responses occurred. Patients with histologically proved lymph node involvement at the time of surgery underwent radiation therapy of 50 Gy to the mediastinum and supraclavicular fossae. Three postoperative deaths occurred, two caused by empyema and one caused by pulmonary embolism. Median survival was 31 months, with a 3-year survival rate of 49%.
A report by Elias and co-workers (1997) from the Brigham and Women's Hospital describes the use of cisplatin, 5-fluorouracil, and leucovorin before thoracotomy, followed by thoracic irradiation of 54 to 60 Gy. Thirty-four patients with N2 disease were treated; 28 patients received a thoracotomy, and complete resection was obtained in 21 patients (75%). Mean survival time was 18 months, and 6 patients remain alive and disease free with a median follow-up of 47 (range, 33 to 50) months.
From these phase II trials, it is safe to conclude that the neoadjuvant regimens described are at least reasonably well tolerated and produce meaningful response rates. A suggestion of improved long-term survival exists in this group of patients after surgical resection and especially in the subset of patients who achieve a pathologic complete response. This further underscores the importance of identifying better chemotherapeutic agents that can achieve a higher percentage of responses.
An early phase II trial looking at one of the newer combinations was carried out by the Swiss Group for Clinical Cancer Research and reported by Betticher and colleagues (2003). This study of docetaxel and cisplatin as induction therapy for biopsy-proven stage IIIA disease has shown an impressive 60% negative mediastinal lymph node rate at surgery.
Based on the feasibility of neoadjuvant therapy and the encouraging results obtained in patients with locally advanced disease (see the subsequent randomized trials), the logical next step has been to try this regimen in patients with less advanced disease, specifically stage IIB disease. These patients, though a more favorable group than patients with stage IIIA disease, still have less than a 50% 5-year survival and thus a multimodality approach might be justifiable. The Bimodality Lung Oncology Team (BLOT) trial that was reported by Pisters and coinvestigators (2000) was a multiinstitutional trial that looked at neoadjuvant chemotherapy using paclitaxel and carboplatin in stages less than IIIA (N2) disease. In addition to two preoperative doses, three postoperative doses were planned for those undergoing complete resection. Fifty-six percent of patients had a major response to the induction therapy, and 81 of 88 undergoing thoracotomy had a complete resection. There were only two postoperative deaths, and 6% had a pathologic complete response. As in many of the aforementioned studies, only 45% received the planned postoperative chemotherapy.
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At the time of publication, the median survival had not yet been reached.
The phase III trial that has been organized on the basis of the encouraging results of the BLOT trial is trial S9900. This study is ongoing and is randomizing patients with stages IB to IIIA (T3, not N2) to preoperative chemotherapy with paclitaxel and cisplatin or surgery alone. This should provide the definitive answer as to whether preoperative chemotherapy increases overall survival enough to justify the delay in operation in a group classically treated with operation alone.
Neoadjuvant Chemotherapy: Randomized Trials
The most compelling data in support of induction chemotherapy come from two randomized phase III trials; these have been conducted by Rosell (1994a, 1994b) and Roth (1994) and their associates. These two studies evaluated 60 patients each with stage IIIA NSCLC. Both studies included patients with clinical N2 disease as well as those with T3N0 or N1 lesions. Patients were randomized to receive either surgery alone or three cycles of platinum-based chemotherapeutic regimens followed by surgery.
The M. D. Anderson study by Roth and colleagues (1994) compared 60 patients randomized to preoperative chemotherapy followed by operation and then three more cycles of chemotherapy versus surgery alone. The chemotherapy consisted of cyclophosphamide, etoposide, and cisplatin. A significant improvement in survival occurred in those patients randomized to the combined-therapy regimen. Results indicated a response rate of 35% in the perioperative chemotherapy arm and 56% survival at 3 years. The 3-year survival rate in the surgical arm of the study was 15%, with six patients surviving to 3 years or more in the chemotherapy arm. Median survival in the surgery-only group was 11 months, versus 64 months in the combined-therapy group (P 0.008). This is all the more interesting considering that fewer than 40% of the patients in each group underwent complete resection (39% in the combined-therapy group versus 31% in the surgery-only group).
Criticisms of this trial are several. First, survival in the surgery-only group was significantly shorter than would be expected, making the survival difference between the groups seem more striking than it might otherwise be. Further, patients with left lung tumors and left paratracheal disease were excluded, because these patients' tumors were felt to be unresectable. The numbers are small, and all of the patients, before entry, had to be judged to be potentially resectable. This would be likely to inject significant selection bias. What is not known is how many patients were screened to find the 60 patients who were ultimately randomized.
Rosell and colleagues (1994a, 1994b) in Barcelona randomized 60 patients with stage IIIA disease, 44 of whom had N2 disease. One group was treated with operation and postoperative radiation therapy of 50 Gy, whereas the other group received neoadjuvant chemotherapy consisting of mitomycin, ifosfamide, and cisplatin. This study was terminated early when an interim analysis demonstrated a highly significant difference in survival. Median survival was 26 months in patients treated with the combination preoperative regimen, compared with 8 months in patients undergoing operation and radiation therapy alone (P < 0.001). The median period of disease-free survival was 20 months in the former group, compared with 5 months in the latter group (P < 0.001). In each group, 90% of the patients underwent resection. The preoperative regimen was well tolerated, with no chemotherapy-related mortality, although two patients in each treatment group died postoperatively.
This trial has been criticized because the control group had an unexpectedly short survival time, even for patients with stage IIIA disease. Additionally, Rosell and co-workers (1995) analyzed the tumor specimens for the presence of mutated K-ras oncogenes as a marker of poor prognosis. The investigation suggested that mutated K-ras constitutes an additional significant prognostic factor beyond the tumor, node, metastasis (TNM) classification. The surgery and radiation therapy group had tumors with a higher incidence of K-ras (42% vs. 15%) and aneuploid cellular content (70% vs. 29%), suggesting that there may have been inhomogeneity between the two patient groups, which Lee and Ginsberg (1997) believed could have influenced the results.
Another randomized trial of neoadjuvant chemotherapy for IIIA disease yielded a trend toward improved survival, but this did not reach statistical significance. At the National Institutes of Health, Pass and associates (1992) randomized 27 stage IIIA patients with documented mediastinal adenopathy to two treatment arms. The study had originally intended to accrue 148 patients. Thirteen patients were treated with preoperative platinum and etoposide, followed by surgery and a postoperative course of the same chemotherapy. The other 14 patients received only 54 to 60 Gy of postoperative irradiation. The resectability rate was approximately 85% in both groups, with no operative mortality. Eight of the 13 patients receiving platinum and etoposide responded, as evidenced by a 50% or greater radiographic tumor shrinkage after two cycles, with one histologically confirmed complete response. The median survival time and disease-free interval for the induction chemotherapy arm were 28.7 months and 12.7 months, respectively, versus 15.6 months and 5.8 months for the control arm. The differences, however, were not statistically significant with this small group of patients (Table 112-7).
A larger, European phase III trial reported by Depierre and colleagues (2002) randomized 355 patients to neoadjuvant mitomycin, ifosfamide, and cisplatin or surgery alone; 167 of the patients were in stage IIIA, and these patients also received postoperative radiation. This study also showed a trend toward improved survival in the neoadjuvant group,
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but the trend did not reach statistical significance. Further, most of the survival advantage was seen in earlier (stages I to II) disease rather than in the stage IIIA group.
Table 112-7. Neoadjuvant Chemotherapy for Non Small-Cell Lung Cancer, Randomized Trials | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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An earlier attempt at a randomized trial reported by Dautzenberg and co-workers (1990) was actually stopped early due to discouraging results. In 1985, investigators in France began to assess cisplatin, cyclophosphamide, and vindesine (PCV) preoperative chemotherapy in patients with resectable NSCLC. Patients were randomized to receive either two preoperative courses of PCV chemotherapy, operation, and two postoperative courses of PCV or immediate surgery. There were 26 randomized patients, 13 in each group. In the chemotherapy arm, 11 patients agreed to receive the two preoperative courses of chemotherapy. The results were disappointing, however, because the reduction in tumor volume in the PCV group did not reach statistical significance. A response was observed in 5 patients (45%), and a progression was observed in 4 patients, leading to a cancellation of operation in 2 of them. Although no death could be related to the chemotherapy, it was decided to stop entering new patients into this trial because of the rate of progression. The authors concluded that in future trials of perioperative or preoperative chemotherapy, medical staging should be planned after the first cycle and after the second cycle of chemotherapy to monitor progression early enough so that surgical resection is still feasible.
Neoadjuvant Chemoradiation Therapy
Although a standard induction regimen remains to be defined, a number of studies have been performed in which preoperative radiation therapy has been used in addition to chemotherapy to improve response rates (Table 112-8). The rationale for chemotherapy alone is that it potentially allows greater dose intensity, as well as the use of some drugs, such as mitomycin, that cannot be administered with radiation therapy. However, pathologic complete response rates with preoperative chemotherapy alone in patients with N2 disease has generally been disappointing, at less than 10%. It has been believed, and confirmed, that adding radiation to the chemotherapy would increase these complete response rates, hopefully translating into improved overall survival. As expected, however, the more aggressive trimodality strategy of chemoradiation therapy followed by surgery can be more toxic, as noted by Reboul and associates (1996) and Lilenbaum and Green (1994).
Table 112-8. Neoadjuvant Chemoradiation Therapy for Non Small Cell Lung Cancer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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One of the earliest experiences with neoadjuvant chemoradiation therapy was reported by Spain (1988, 1993). From 1981 to 1985, 31 patients with locoregionally advanced disease were enrolled in a study of neoadjuvant therapy with MVP and continuous thoracic irradiation (n = 26). Spain (1993) reported that a median follow-up from the initiation of therapy was 81 months; median survival was 19 months, with 3- and 6-year survival rates of 33% and 23%, respectively.
Between 1981 and 1984, investigators at the Dana-Farber Cancer Institute treated 41 patients with pathologically determined marginally resectable stage IIIA disease. Included within this group were patients with T3N0 disease and patients with N2 mediastinal metastases. Patients received two cycles of perioperative CAP chemotherapy followed by a radiation dose of 30 Gy. A complete resection was accomplished in 36 (88%) of 41 patients. Postoperative radiation therapy and four more cycles of CAP were used in all cases. Tumor shrinkage was observed in 53% of patients. Skarin and associates (1989) reported that the median survival was 32 months and the 1-year and 5-year survival rates were 75% and 31%, respectively. Eighteen (66%) of 36 patients failed systemically, and 4 patients failed locally. A later, similar phase II study at Dana-Farber resulted in an overall 5-year survival of 22% reported by Elias and co-workers (1994).
Another early nonrandomized trial of combined neoadjuvant chemoradiation came from the LCSG. LCSG 831 treated 39 patients with clinical stage III disease. The patients received three cycles of chemotherapy with CAP and 30 Gy of irradiation in 300-cGy fractions. The overall response rate to induction therapy was 51%. Thirty-three percent of patients subsequently were able to undergo a
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complete resection. Eagan and associates (1987) reported an overall survival of 8% at 2 years, with a median survival of 11 months. Interestingly, no statistically significant survival differences occurred between patients not having thoracotomy and those who had thoracotomy or even those with complete tumor excision. The patients who received chemotherapy, chest irradiation, and surgical resection had a low incidence of local or regional failure (5%), but distant disease remained problematic.
The difference in patient outcome in this trial compared with the Dana-Farber trial may be caused primarily by patient selection; the latter trial included T3 (chest wall) cases and excluded patients with extracapsular N2 disease. Thus, the Dana-Farber trial had a more favorable stage III subset mix than the LCSG trial. Furthermore, the LCSG trial did not allow resection for postinduction stable disease; the surgical resection possibly had a favorable effect on this subgroup in the Dana-Farber trial.
Compared with the Dana-Farber experience and LCSG 831, the next three trimodality trials used higher cisplatin doses and enrolled more patients. LCSG trial 852, reported by Weiden and Piantadosi (1991, 1994), used neoadjuvant cisplatin, 5-fluorouracil, and partially concurrent low-dose radiation therapy (3,000 cGy in 15 fractions) in 85 patients with stage IIIA (80%) or stage IIIB (13%) disease. Only 2 patients achieved a complete response, but 46 achieved a partial response, with an overall response rate of 56%. Fifty-four (64%) underwent thoracotomy, but only 34% had complete resections. Median survival of all patients was 13 months. The investigators concluded that this neoadjuvant regimen did not provide major benefit in patients with advanced but potentially resectable NSCLC. What became apparent from this study, however, was that neoadjuvant chemoradiation therapy altered the usual pattern of disease recurrence. Patients whose tumors were completely resected were less likely to have isolated local recurrences initially (17% vs. 46%) and were more likely to have metastatic disease in the brain (17% vs. 5%) than were patients whose tumors could not be completely resected.
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Strauss and associates (1992) reported the treatment and results of the CALGB 8634 study of neoadjuvant treatment on 41 patients with mediastinoscopically confirmed stage IIIA NSCLC (80% N2; 20% T3N0 or T3N1). The patients received two cycles of preoperative chemotherapy with cisplatin, vinblastine, and 5-fluorouracil along with concurrent 30-Gy chest irradiation in 15 fractions. Resection was performed in 76% of the patients, followed by another cycle of chemotherapy and 30-Gy chest irradiation. A total of 61% of patients had completely resected disease. Three treatment-related deaths occurred. Median survival was 15.5 months, and 1-year survival was 58%.
One of the largest phase II trials, the SWOG 8805 study, published by Albain (1995) and Rusch (1993) and their colleagues, used concurrent induction chemotherapy and radiation therapy in 154 patients with stage IIIA and IIIB disease. Cisplatin was administered on days 1, 8, 29, and 36; etoposide on days 1 to 5, 29 to 33; and 45 Gy of radiation therapy was given over 5 weeks. Two notable differences between the SWOG trial and early neoadjuvant trials were the use of higher-dose, continuous radiation therapy and the concurrent administration of the chemotherapy and the radiation therapy. All patients had pathologically confirmed N2 or N3 disease (IIIA, n = 75; IIIB, n = 51). Surgical resection was performed 2 to 4 weeks after completion of the induction therapy in patients demonstrating tumor regression or stable disease. Of the 154 patients, 127 were eligible for resection. Complete resection was accomplished in 74% of patients taken to the operating room. Although there was an 8% incidence of postoperative death, no tumor was found in 22% of the resections. Median survival in stages IIIA and IIIB was essentially the same at 13 and 16 months, respectively. Three-year survival was 26% and 24% in these groups.
In an important finding that has been confirmed by several subsequent studies, SWOG 8805 demonstrated that patients with a pathologic complete response in the lymph nodes had a 30-month median survival, compared with 10 months for those with persistent lymph node disease (P < 0.0005). In fact, the strongest predictor of long-term survival was lack of positive mediastinal nodes at surgery, with a 3-year survival rate of 44% versus 18% in those who had persistent nodal disease (P = 0.0005). The investigators did, however, note substantial toxicity. Two treatment-related deaths (1.6%) occurred during the induction therapy period. During the postoperative period, 11 (8.4%) additional deaths occurred. Most of the lethal toxicities were drug related. Rusch and Feins (1994) concluded that instituting neoadjuvant therapy not only for IIIA but also for IIIB NSCLC was feasible.
The Rush-Presbyterian group, as reported by Bonomi (1993), has performed two sequential neoadjuvant trials of low-dose cisplatin chemotherapy and concurrent radiation therapy in patients with clinical stage III disease. In the first 64 patients reported by Taylor and associates (1987), 5-fluorouracil was added to the cisplatin. In the second trial, 64 patients also received etoposide, as recorded in the publications of Reddy (1992), Recine (1990), Faber (1989), Bonomi (1986), and Pincus (1988) and their co-workers. All patients received 40 Gy of split-course radiation therapy administered concurrently with the four cycles of induction chemotherapy. Bonomi (1993) recorded that the toxicity of the induction regimen was significant. The third trial (n = 45) used the same dosages of chemotherapy, but the radiation dosage was altered to 150-cGy fractions given twice daily. Of the 128 patients entered into the first two studies, 85 were considered potential candidates for surgical resection, and 73% ultimately went to thoracotomy. The overall response rate, complete and partial, was 67% (86 of 128). Histologic absence of tumor was observed in 22% of resected specimens, which did not correlate with disappearance of disease documented by imaging studies. The complete resection rate was 68%, and the operative mortality was 5%. The overall survival rate for all 85 patients was 40% at 3 years, with a median survival of 21 months. The addition of etoposide to the induction regimen in the second trial (n = 29) did not increase the response or resectability rates significantly. The Kaplan-Meier survival estimate for all 128 patients revealed a median survival of 22 months and a projected 5-year survival rate of 34%.
A trial presented by Favaretto and colleagues (1996) enrolled 39 patients with stage III disease. Treatment consisted of two courses of cisplatin and etoposide plus radiation therapy delivered in two cycles of 2,560 cGy each. After operation, three additional chemotherapy courses were planned. The complete response rate was 67%, and a resection was completed in 20 (51%) patients. Of the 23 patients who attained a complete response, 5 relapsed locally and 11 had distant disease. Median survival was 16 months, with 18% 3-year survival and 13% 5-year survival. Resected patients had a median survival of 21 months, versus 10 months for unresected patients (P = 0.01). Again, no significant difference was evident between stage IIIA and stage IIIB disease.
At the Massachusetts General Hospital, 42 biopsy-proven patients with N2 disease were treated by Choi and associates (1997) with two courses of cisplatin, vinblastine, 5-fluorouracil, and 42-Gy radiation therapy followed by operation followed by another course of twice-daily chemoradiation therapy. Treatment-related mortality was noted in 7% of patients. Mean survival was 25 months, with an actuarial 5-year survival of 37%. Importantly, concurrent chemoradiation therapy resulted in 67% tumor downstaging, compared with 13.5% in the CALGB 8935 trial reported by Sugarbaker and associates (1995), 28% in the University of Toronto experience reported by Burkes and colleagues (1992), and 30% in the Memorial Sloan-Kettering Cancer Center experience reported by Martini and co-workers (1993). Results are difficult to interpret because of small patient numbers. However, Choi and associates' (1997) study suggested the possible added benefit of twice-daily radiation therapy given with concurrent chemotherapy.
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Bedini and associates (1993) in Italy reported on a phase II study of 38 patients, 27 of whom had nonresectable stage IIIB disease. They used concurrent continuous infusion of cisplatin given at a daily dose of 6 mg/m2, plus radiation therapy of 50 Gy. Treatments were given on an outpatient basis by means of a central venous catheter and a portable infusion pump. Thoracotomy was carried out in 18 patients. Partial or complete locoregional response at 4 weeks after treatment completion was 83%. Eighteen patients were resected. Overall 1-, 2-, and 3-year progression-free survival probabilities were 42%, 24%, and 21%, respectively.
Another use of continuous-infusion cisplatin involved 53 patients with stage IIIA disease treated with a multimodality approach consisting of induction radiation therapy (55.8 Gy) and two cycles of concurrent chemotherapy with cisplatin for 4 days given by continuous infusion and bolus etoposide, on days 2 and 4 of each cycle, followed by operation and additional adjuvant chemotherapy (Weitberg et al, 1993). Of the 53 evaluable patients, 47 achieved clinical responses after induction therapy, and complete surgical resection was accomplished in 27 patients. The median survival of the entire group was 24 months; the median survival of the resected patients had not been reached at the time of publication.
In a retrospective analysis, Yoneda and colleagues (1993) reported on 25 patients with stage III NSCLC who were treated with cisplatin-based chemotherapy and thoracic irradiation (50 to 75 Gy) followed by surgery. Eighteen patients underwent curative resection. Severe postoperative complications occurred in 5 patients (20%), with one death reported. Disease recurred in 5 of the 18 patients who underwent a curative resection. The estimated 3-year survival was 67% for all patients. The treatment-related morbidity in this study seems excessive, perhaps due to the high preoperative dose of radiation in some patients.
Despite the relatively encouraging results observed with preoperative chemoradiation therapy, the majority of patients eventually died of metastatic disease. In recent years, the availability of taxanes has resulted in a number of studies incorporating these agents into the neoadjuvant regimens. According to Bonomi (1998), these agents produced improved 1-year survival rates in phase II trials, and they have been shown by Natale (1997, 1998) to enhance the effect of radiation therapy in vitro.
Investigators at Rush-Presbyterian initiated a trial adding paclitaxel to an etoposide/platinum and radiation regimen. Bunn (1997) and Bonomi and associates (1995) have enrolled all stage IIIA and selected stage IIIB patients considered eligible for pulmonary resection after two courses of chemoradiation therapy (40 Gy). Preliminary results demonstrated that pulmonary resection is feasible after treatment with radiation therapy and concurrent paclitaxel-containing chemotherapy. Patient accrual by Bonomi (1998) and Bonomi and colleagues (1996) is ongoing. The relatively high incidence of postoperative bronchopulmonary complications as noted by Bonomi and associates (1997) suggests, however, that the toxicity of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic irradiation needs careful evaluation.
Other groups, such as those of Pisters (1997) and Palackdharry (1997) and their co-workers, are exploring the use of paclitaxel in the neoadjuvant setting either as a single agent or in combination. As the data mature in trials such as these, they may serve as the basis for future randomized neoadjuvant trials utilizing these newer agents.
It is difficult to draw conclusions based on these trials because considerable differences in enrollment criteria exist. The LCSG and SWOG trials included both stage IIIA and IIIB, whereas the Rush-Presbyterian trial included patients with stage IIIA (now IIB) but not N2, and a few patients had stage IIIB tumors. Another difficulty involves the measurement of response. Certain investigators determine response based on radiologic appearance, whereas others base it on pathologic response. They are not necessarily equivalent and are not even always stated.
In an attempt to definitively determine if adding chemotherapy to surgery and radiation therapy improves survival compared with radiation therapy and surgery alone, CALGB 9134 has been undertaken, as noted by Rusch and Feins (1994). A target of 250 patients with stage IIIA disease will be randomized to two possible treatment strategies. The first will receive a radiation dose of 40 Gy followed by surgery and an adjuvant 20 Gy of irradiation. The other arm will receive preoperative and postoperative cisplatin, etoposide, and granulocyte colony-stimulating factor immunotherapy in addition to 40 Gy adjuvant radiation therapy. As of this writing, the study results have yet to be published.
An important intergroup trial (0139) currently is attempting to determine the role of surgical resection in the combined modality treatment of patients with stage IIIA biopsy-proven T1 3N2 disease. As reported by Martini (1997) and Albain (1995) and their associates, as well as by Albain (1997), in this trial all patients receive induction radiation therapy of 45 Gy over 5 weeks and concurrent cisplatin and etoposide for two cycles 28 days apart. Before this induction therapy, patients are randomized to receive either surgical resection afterward, if feasible, plus two additional cycles of chemotherapy, or additional radiation therapy (60 Gy total) plus two additional cycles of chemotherapy. The target for enrollment is 512 patients. Results of this trial are eagerly anticipated.
It should also be mentioned that the EORTC has an ongoing phase III trial addressing a similar issue. EORTC 08941 randomizes stage IIIa patients to surgery with or without radiation therapy versus radiation alone after response to neoadjuvant platinum-based chemotherapy.
The evidence from most phase II studies would suggest that surgery does have an added benefit beyond chemoradiation alone. For example, Sugarbaker and colleagues (1995) reported the results of CALGB 8935, which evaluated
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patients with mediastinoscopically staged N2 disease undergoing cisplatin and vinblastine neoadjuvant chemotherapy, with additional chemotherapy and radiation following resection. Those who underwent a complete resection had a 46% 3-year survival, those who underwent incomplete resection had a 25% 3-year survival, and those who underwent no resection had a 0% 5-year survival.
CONCLUSION
Outside of protocols, the current optimal management of patients with early NSCLC, stages I and II, consists of surgical resection alone. The phase III intergroup study S9900 will address whether there is a role for neoadjuvant chemotherapy in those with stages IB through IIIa (non-N2), and physicians should be encouraged to enroll their patients in this study. Currently, stage IV patients (outside of those with solitary brain and perhaps adrenal metastases) are essentially incurable. The main issue in these patients is palliation, and chemotherapy has been demonstrated to extend life by a few months and to improve quality of life in selected stage IV patients. Radiation may be indicated in symptomatic stage IV patients or those with brain metastases.
At present, despite considerable optimism regarding some of the newer agents, one must conclude that neither radiation therapy nor chemotherapy nor a combination of the two can be recommended as standard treatment after a complete resection of NSCLC, even with locally advanced disease. Currently, no evidence exists that any of these regimens definitively improves survival when used in the adjuvant setting. Outside of a clinical trial, then, postoperative adjuvant therapy cannot be recommended at this time.
Between the extremes of stages I and IV, the entire group of stage III tumors remains an arena of intense debate, particularly with regard to neoadjuvant treatment, despite the large number of trials that have been completed. This accounts for a large group, because approximately 40% of patients present at this stage. Concurrent chemotherapy and radiation therapy has become the most common form of treatment for stage IIIA NSCLC when it is believed to be unresectable. This type of combination therapy is certainly the sole treatment recommended for most patients with stage IIIB disease, where most feel that operation has little role in management. Many currently believe that induction chemotherapy is indicated in stage IIIA patients with mediastinal lymph node (N2) disease, although the two positive randomized trials by Rosell (1994a, 1994b) and Roth (1994) and their colleagues remain controversial.
In both stage IIIB patients treated nonoperatively and stage IIIA patients being considered for neoadjuvant treatment, however, it has been difficult to define the best regimens because considerable differences exist among the completed clinical trials with respect to eligibility criteria, accuracy of pretreatment staging, and induction regimens. Further, although all but the most recent clinical trials have used cisplatin-containing regimens, the agent currently favored is carboplatin. This agent, when combined with paclitaxel, is the current regimen of choice for patients with disseminated disease and is currently being evaluated in phase II neoadjuvant trials as well.
Thus, the standard combination regimen has changed, as noted by Feld (1996), Johnson (1994), and Lee and Ginsberg (1997), since most of the phase II and both of the phase III neoadjuvant trials have been reported. Even the current intergroup trial (0139) looking at the role that operation plays in the management of patients with N2 disease uses a chemotherapy regimen, cisplatin and etoposide, that currently is no longer in favor.
Platinum-based regimens, the gold standard of NSCLC chemotherapy since the mid-1980s, ultimately may not be as active as other regimens that include agents such as epirubicin, docetaxel, irinotecan, topotecan, gemcitabine, vinorelbine (Navelbine), and edatrexate, as suggested by many investigators, such as Saijo (1998) and Natale (1997, 1998), as well as by Bonomi (1996), Cerny (1994), and Murphy (1993) and their colleagues. Various combinations of these agents, some without a platinum compound but often with paclitaxel, are currently in clinical trial. Further, very recent promising developments with novel agents such as tyrosine kinase inhibitors, antisense therapies, and antiangiogenic therapies may come to play a role in the not too distant future.
Future studies will attempt to incorporate novel schemes for the treatment of locally advanced NSCLC. Novel radiation therapy fractionation regimens have been an area of continued investigation. The Radiation Therapy Oncology Group published a randomized trial of hyperfractionated radiation therapy showing some improved survival at higher doses. Continuous hyperfractionated accelerated radiation therapy is another novel regimen in which multiple fractions of irradiation are given each day, and the entire course is completed over a shorter period. It remains to be seen how operation and these new radiation therapy techniques are combined.
Induction radiation therapy alone is likely not indicated in the treatment of any stage NSCLC. No survival benefit has ever been demonstrated. Preoperative radiation therapy in patients with so-called Pancoast's tumors has classically been used but has never been subjected to a prospective trial to assess its efficacy. A recently reported phase II intergroup trial (9416) by Rusch and associates (2001) of neoadjuvant chemoradiation followed by resection for these tumors, however, resulted in substantially better outcomes than historic controls. Thus, preoperative chemoradiation is likely becoming the standard for this particular condition. Dillman and associates (1990), as well as many others, believe that in combination with chemotherapy, radiation therapy likely will find a role within an effective induction regimen for stage IIIA NSCLC as well.
Of great importance is the consideration of quality of life in patients undergoing these combined regimens, an area
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that has not been adequately addressed up to the present time. Quality-of-life measurement tools are available to incorporate into future studies, so additional information should be forthcoming. Toxicity from these preoperative regimens can be substantial, especially if an element of postobstructive pneumonia exists. This further underscores the importance of continuing to evaluate multimodality therapy for N2 disease in protocol settings.
In an interesting review by Mackillop and co-workers (1987), 118 Canadian physicians who treat lung cancer were asked how they would wish to be managed if they had NSCLC. Although opinion was divided as to the role of immediate radiation therapy in inoperable cancer and the role of postoperative radiation therapy following incomplete surgery, there was little controversy as to the role of chemotherapy. Only 3% of doctors wanted adjuvant chemotherapy after surgery for early disease, 9% wanted chemotherapy for advanced disease confined to the chest, and 15% wanted chemotherapy for symptomatic metastatic disease. A similar questionnaire by Palmer and associates (1990) was sent to 461 American and Canadian physicians. This series reported no consensus as to preferred treatment in clinical situations. It is hoped that with better chemotherapeutic or even biological agents available today or becoming available in the near future, the answers will be different.
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