3.2.2 Chemotherapy or Chemoradiotherapy Followed by Surgical Resection
for Non-Small Cell Lung Cancer
Nena Mirkovic and Kathy S. Albain
N. Mirkovic, MD
Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA K. S. Albain, MD
Department of Medicine, Division of Hematology/Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
The integration of chemotherapy with or without radiotherapy together with surgery in a combined- modality approach for non-metastatic non-small cell lung cancer has been the focus of intense clinical research over the past two decades. Many questions are debated, including whether preoperative therapy should be used at all in early stage disease or whether a surgical resection should ever be performed af- ter combined-modality treatment of more advanced stage III cancers. If the answer to either of these is
‘yes,’ then questions remain regarding which patient population should be treated and with what specifi c induction regimen.
Induction therapy followed by surgery is dis- cussed for two distinct patient populations with dif- ferent rationales and expectations. The fi rst group involves patients with stages I, II and selected early stage III NSCLC. The standard of care in this group of patients has been surgical resection. However, de- spite complete resection of all known disease, many of these patients remain at high risk for relapse and death. Distant metastases are the most common site of relapse in this patient population. The addition of systemic therapy prior to surgery in this patient population has the aim of decreasing the rate of distant spread and thus improving their survival.
Radiation therapy plays limited role in this group of patients.
The second large group for which a combined- modality treatment plan that incorporates surgery may be benefi cial includes patients with locally advanced disease, for whom the current standard of care is concurrent chemotherapy and radio- therapy (chemoRT). Cure rates produced with this chemoRT alone are modest, with long-term survival in reported randomized phase III trials between 8%–15% (Sause et al. 2000; Dillman et al. 1996).
Both local and distant failure rates are very high.
The rate of persistent local disease was reported to be as high as 83% after treatment with chemo- therapy and full-dose radiotherapy (Arriagada et al. 1991). Persistent locoregional disease is a major problem, not only because of the local effects of the
CONTENTS
3.2.2.1 Radiotherapy as Sole Induction Modality 224 3.2.2.2 First-Generation Induction Trials
Incorporating Chemotherapy 224
3.2.2.3 Second-Generation Phase II Induction Trials 225 3.2.2.3.1 Chemotherapy as the Sole Induction Modality 225 3.2.2.3.2 Chemotherapy and Radiotherapy
as Induction Modalities 227
3.2.2.3.3 Long-Term Survival in the Second-Generation Induction Trials 228
3.2.2.4 Third-Generation Phase II Studies of Induction Chemotherapy plus Concurrent Hyperfractionated Radiotherapy 229 3.2.2.5 Predictors of Favorable Outcome in Second-
and Third-Generation Phase II Studies 231 3.2.2.6 The Stage IIIB Subset in Induction Trials 232 3.2.2.7 Patterns of Failure in Second- and
Third-Generation Phase II Induction Trials 233 3.2.2.8 Randomized Trials of Surgery Alone Vs
Induction Therapy Followed by Surgery in Resectable IIIA NSCLC 233 3.2.2.9 Radiotherapy as a Component of the Induction Regimen 235
3.2.2.10 Phase III Trials of Chemoradiotherapy With or Without Surgery 236 3.2.2.10.1 Induction Chemotherapy Followed by
Surgery vs Radiotherapy Alone 236 3.2.2.10.2 Induction Chemotherapy vs Induction Radiotherapy 237
3.2.2.10.3 Induction ChemoRT Followed by Surgery vs Defi nitive ChemoRT Alone 237 3.2.2.11 Phase II Trials of Induction Regimens
That Incorporated Third-Generation Chemotherapy Agents 238
3.2.2.12 Treatment-Related Morbidity and Mortality in Trials of Induction Therapy Followed by Surgery 240 3.2.2.13 Strategies to Reduce Radiotherapy-Related
Morbidity in Trimodality Treatment of Non-Small Cell Lung Cancer 241
3.2.2.14 Ongoing and Planned Phase III Trials Worldwide 242 3.2.2.15 Conclusions 242
References 243
uncontrolled tumor but also as a potential source of metastatic seeding. Persistence of local disease after completion of treatment portends especially poor prognosis (Andre et al. 2001). It is hypoth- esized that surgical removal of residual disease should render a proportion of these patients dis- ease-free.
The optimal sequence of chemotherapy, radio- therapy, and surgery is uncertain. Compliance with induction therapy (same as older term “neoadju- vant”) is generally higher than with adjuvant treat- ments (either chemotherapy or RT), due to poor tolerance of therapy in patients recovering from thoracotomy. Other potential advantages of early administration of systemic therapy include im- proved respectability, organ sparing (less frequent need for pneumonectomy) and the opportunity for in vivo chemosensitivity testing. Perhaps the most important, yet not fully validated, advantage of the induction therapy option is the delivery of systemic therapy in the moment of the lowest micrometa- static burden. The disadvantages to a neoadjuvant strategy include compromised nutritional and im- munological status prior to major surgery, compli- cations arising from the induction regimen causing a delay of defi nitive surgery, early tumor progres- sion, technically challenging surgery (especially if RT is incorporated in the induction program), and poor postoperative healing.
In this chapter we review the development and current status of combined-modality treatment programs that include surgical resection. A large number of phase II trials and several phase III tri- als involving bimodality or trimodality treatment have been completed, and a few more are ongo- ing. Direct comparison of these studies is impos- sible due to differences in methodology and patient population entered in these trials. Some of the stud- ies enrolled advanced stage patients with the dual aims of decreasing systemic spread while improv- ing the resection rate. Other trials enrolled patients with lower volume disease technically amenable to upfront resection. Pathological staging of the medi- astinum was not uniformly mandated across trials, and the induction regimens varied greatly regard- ing specifi c chemotherapy and RT prescriptions.
Criteria proceeding to a post-induction resection were also not uniform. Eligibility for thoracotomy was in some studies reserved only for patients with a response while other studies required re- section of “stable” disease as well. Data regarding local and distant relapse, postoperative morbidity and mortality, late causes of death and predictors
of favorable outcome were not always reported.
Nevertheless, much can be learned from the trials conducted to date.
3.2.2.1 Radiotherapy
as Sole Induction Modality
Early induction trials focused on preoperative ra- diotherapy alone because effective chemotherapy did not exist. A large randomized study published in 1975 found no difference in overall survival (Warram 1975). Patients enrolled were initially considered to be operable, and were assigned to either preoperative radiotherapy or immediate surgery. Even though 27%
of the patients had no tumor in the resected speci- men, resectability rates were not improved and over- all survival was identical. The last randomized trial that used radiotherapy alone as induction treatment was CALGB 9134 (Elias et al. 2002). This trial closed early due to poor accrual and long-term results were not encouraging. Given the propensity of NSCLC for distant spread, the induction strategy consisting only of local treatment is no longer considered appro- priate and induction radiotherapy alone has been largely abandoned.
3.2.2.2
First-Generation Induction Trials Incorporating Chemotherapy
The initial set of small pilot studies was conducted in the 1980s. These trials were primarily aimed to defi ne the feasibility and safety of pre-surgery induc- tion treatment. Patients enrolled had stage III disease, mostly based on clinical staging, and pathologic con- formation of mediastinal disease was not universally required. Some trials enrolled patients with high- volume disease, while the others enrolled only low- burden disease. The designs of the trials are reviewed in Table 3.2.2.1 (Skarin et al. 1989; Eagan et al. 1987;
Bitran et al. 1986; Elias et al. 1994; Darwish et al.
1994). Radiotherapy varied from preoperative, post- operative, or both, and in most cases was sequenced after the chemotherapy.
The outcomes of these trials, reviewed in
Table 3.2.2.2., were highly variable but in general
demonstrated safety and feasibility of combined-
modality treatment in conjunction with surgery.
3.2.2.3
Second-Generation Phase II Induction Trials 3.2.2.3.1
Chemotherapy as the Sole Induction Modality Induction trials conducted following the fi rst-genera- tion efforts were larger and designed with better stag- ing and in more homogenous patient populations.
Studies in which the induction regimen consisted of chemotherapy alone are outlined in Table 3.2.2.3.
All of these required pathological confi rmation of N2 disease, but the disease burden or tumor volume varied. Three of the studies used the MVP regimen (mitomycin-C, vinblastine, cisplatin), one incorpo- rated vinblastine plus cisplatin and the last trial tested continuous infusion cisplatin and 5-fl uoro-
uracil with leucovorin rescue (Wagner et al. 1994;
Martini et al. 1993; Burkes et al. 1992; Elias et al.
1997; Sugarbaker et al. 1995). Postoperative RT was a part of the treatment plan in all except the LCSG and Toronto trials. In the Dana-Farber and CALGB trials, the postoperative RT dose was 54 Gy for com- pletely resected patients and 60 Gy after an incom- plete resection. In the Memorial study, postoperative RT was recommended, but not mandated, for patients with persistent mediastinal nodal disease at the time of surgery. In that study, some of the patients with incompletely resected tumors received radioactive iodine seed implant.
The outcomes of these studies are summarized in Table 3.2.2.4. The LCSG 881 trial was a two-arm phase II randomized trial, in which one arm was assigned preoperative chemotherapy and the other received
Table 3.2.2.1. Designs of fi rst-generation phase II induction trials for NSCLC Investigators Stage subsets/
tumor volume
Treatment program Number
of patients
Biopsy-proven N2/N3 disease (%)
Dana Farber I (Skarin et al. 1989)
T3 or low-volume stage III(N2)
CAP × 2 → RT → surgery → RT
→ CAP × 3
41 68
LCSG 831 (Eagan et al. 1987)
T3 or low-volume stage III(N2)
CAP × 3 with split RT → surgery 39 51
University of Chicago (Bitran et al.1986)
High-volume T3 or T4N2 or N3
VdEP × 2→ surgery → RT 21 100
Dana Farber II (Elias et al. 1994)
T1-3N2 (mixed low
and high volume) CAP × 4 + RT→ surgery → RT
54 94
Perugia
(Darwish et al. 1994)
T1-3N2 (clinically high tumor volume)
EP × 2–3 → surgery → variable RT 42 0
LCSG, Lung Cancer Study Group; C, cyclophosphamide: A, doxorubicin; P, cisplatin; RT, radiotherapy: Vd, vindesine; E, etopo- side; RT, radiotherapy.
Table 3.2.2.2. Results from fi rst-generation phase II induction trials for NSCLC
Investigators
Response rate (%)
Resection rate (% original n)
Median survival (months)
Long-term survival
Dana Farber I (Skarin et al. 1989) 43 88 32 31%, 3-year
LCSG 831 (Eagan et al. 1987) 51 33 11 8%, 2-year
University of Chicago (Bitran et al. 1986) 70 14 8 34%, 1-year
Dana Farber II (Elias et al. 1994) 39 56 18 22%, 5-year
Perugia (Darwish et al. 1994) 82 72 24 24%, 3-year
LCSG, Lung Cancer Study Group.
preoperative radiotherapy. The results were reported for the entire group of patients and not separately for each treatment arm. Resection rates (of the en- tire denominator) were 51%–68%. Pathological complete response rates ranged from 0% to 15%.
Postoperative mortality ranged from 0% to 18%. The causes of death were predominantly pulmonary or cardiopulmonary. Postoperative radiotherapy did not provide additional benefi t in the Memorial study (p=0.24), however the selection of patients receiving radiotherapy was based on unfavorable response to neoadjuvant chemotherapy, not by randomized as- signment. Pulmonary complications attributable to
mitomycin-C in the Memorial study, including the three lethal ones, all occurred after the cumulative dose of 24 mg/m2. The studies that did not use mi- tomycin-C had lower perioperative death rates. In the Dana-Farber study, all mediastinal downstaging to N0 or N1 occurred in patients with low-volume disease. The CALGB study noted that there was no correlation between radiographic response to the induction regimen and pathological downstaging at the time of surgery.
Survival outcomes were highly variable, with me- dian survival ranging from 12 to 21 months, due to differences in the study eligibility and design, as re-
Table 3.2.2.3. Design of second-generation trials of induction chemotherapy for pathologic stage IIIA (N2) NSCLC
Investigators Number
of patients
Local disease burden
Treatment schema
LCSG 881
(Wagner et al. 1994)
26 High volume MVP x 2 → Surgery or 44 Gy → Surgery Memorial
(Martini et al. 1993)
136 Mixed volume MVP x 2–3 →Surgery → Radiotherapy for persistent N2 Toronto
(Burkes et al. 1992)
39 Mixed volume MVP x 2 → Surgery → MVP x 2 for responders Dana Farber III
(Elias et al. 1997)
34 Mixed volume PFL (continuous infusion) x 3 → Surgery → Radiotherapy CALGB 8935
(Sugarbaker et al. 1995)
74 High volume VP x 2 → Surgery → VP x 2 → Radiotherapy
LCSG, Lung Cancer Study Group; CALGB, Cancer and Leukemia Group B; M, mitomycin-C; V, vinblastine; P, cisplatin; F, 5- fl uorouracil: L, leucovorin.
Table 3.2.2.4. Results of second-generation trials of induction chemotherapy for pathologic stage IIIA(N2) NSCLC
Investigators Response
rates (%)a
Complete resection rates (%)a
Treatment- related mortality (%)a
Operative mortality (%)c
pCRb rates (%)
pCRb in mediastinal nodes (%)a
Median survival (months)
LCSG 881
(Wagner et al. 1994)
65 68 14.5 18 4 Not stated 12
Memorial
(Martini et al. 1993)
78 65 5 5 14 32 19
Toronto
(Burkes et al. 1992)
71 51 18.0 9 8 Not stated 21
Dana Farber III (Elias et al. 1997)
65 62 0 0 15 44 18
CALGB 8935
(Sugarbaker et al. 1995)
64d 62 2.7 3.2 0 Not stated 15
LCSG, Lung Cancer Study Group; CALGB, Cancer and Leukemia Group B.
a Percent of all enrolled patients.
b Pathological complete response.
c Percent of patients subjected to surgery.
d Includes stable disease.
viewed above. In the Dana Farber study and CALGB trial 8935, 15% and 41% of fi rst relapses occurred in the brain, respectively.
3.2.2.3.2
Chemotherapy and Radiotherapy as Induction Modalities
Another group of second-generation trials conducted during a similar time period used chemotherapy given concurrently with radiotherapy (chemoRT), such that radiotherapy commenced on day 1 of chemotherapy (Albain et al. 1995; Weiden and Piantadosi 1992;
Faber et al. 1989; Strauss et al. 1992; Vora et al.
2000). The designs of these studies are presented in Table 3.2.2.5. Patients eligible for these trials had stage III disease, and the proportion of pathologic N2-positive disease was 38%–87%. All of the trials used cisplatin-based induction chemotherapy, with the addition of etoposide, 5-fl uorouracil, vinblastine, or a combination of these drugs. Radiotherapy was delivered in continuous fashion in all trials, except in the Rush Presbyterian study, in which 40 Gy were delivered over 7 weeks (split course). In the LCSG 852 trial, only the patients with a clinical response were eligible for thoracotomy, but some of the non- responders underwent surgery off the protocol.
Postoperative treatment was variable. In the SWOG 8805 trial, patients with positive node, positive sur- gical margins, or unresectable tumors received two more cycles of chemotherapy with an additional 14 Gy. The Tufts University study gave postoperative
chemotherapy with either cisplatin/etoposide or car- boplatin/paclitaxel. The CALGB study mandated one more cycle of chemotherapy concurrent with 30 Gy of thoracic radiotherapy for all patients.
All the trials except the CALGB study allowed the inclusion of the IIIB subset, and the proportion var- ied from 6% to 53% of patients per trial. The SWOG 8805 and LCSG 852 trials were specifi cally designed for patients with a high-volume disease burden, whereas the others included a mix of high and low burden presentations.
The outcomes of these studies are summarized in Table 3.2.2.6. Clinical response or “response plus stable” (in one study) rates ranged from 56% to 92%. Complete resection rates ranged from 52% to 79% and pathologic complete response rates (pCR) ranged from 9% to 21% of the initial number of pa- tients entered on the studies. In the SWOG 8805 trial, there were 30 patients who had stable disease at the time of presurgical evaluation, and 26 of those under- went a complete resection. Of those 26 patients, 45%
had pCR or only rare microscopic foci. The Rush- Presbyterian trial also found discrepancies between the clinical response to the induction therapy and pathological fi ndings at the time of surgery. Thus, a substantial proportion of patients with a residual mass and/or nodal enlargement on the post-induc- tion CT scan has, in fact, a major response, and sur- gical exploration should not be withheld from them just on the basis of lack of response on the CT scan.
The operative mortality rates in these trials were 0%–15%. The majority of the events were pulmonary, similar to chemotherapy-alone induction trials. The
Table 3.2.2.5. Design of second-generation trials of concurrent induction chemoradiotherapy (standard fractionation) in NSCLC
Investigators Number of patients
Disease burden
IIIA(N2) (%)
T3N0-1/T4 or N3 (%)
Biopsy of N2 or T4 Required?
Treatment schema
SWOG 8805 (Albain et al. 1995)
126 High
volume
60 0/40 Yes EP × 2 + 45 Gy → Surgery → EP × 2 + 14 Gy if persistent N2/incomplete resection LCSG 852
(Weiden et al. 1992)
85 High
volume
85 0/13 No PF × 2 + 30 Gy → Surgery
Rush-Presbyterian (Faber et al. 1989)
85 Mixed
volume
73 21/6 Yes PF or PEF + 40 Gy (split course)
→ Surgery CALGB I
(Strauss et al. 1992)
41 Mixed
volume
80 20/0 Yes PVF × 2 + 30 Gy → Surgery → PVF × 1 + 30 Gy
Tufts
(Vora et al. 2000)
42 High
volume
66 2/45 No EP × 2 + 59.4 Gy → surgery → PE × 4 or Carbo T × 4
SWOG, Southwest Oncology Group; LCSG, Lung Cancer Study Group; CALGB, Cancer and Leukemia Group B; E, etoposide; P, cisplatin; F, 5-fl uorouracil; V, vinblastine; Carbo, carboplatin; T, paclitaxel; Gy, gray.
cause of death often resembled the adult respira- tory distress syndrome (ARDS). The Tufts study was unique in that the ARDS was not observed, despite the high preoperative radiation dose. These investigators used a rigid protocol to limit fl uids intraoperatively and postoperatively, and had the patients ventilated for at least 48 h.
Median survivals for the second-generation studies of concurrent chemoRT ranged from 13 to 26 months. Studies that limited enrollment to pa- tients with high-burden disease reported shorter median survivals than those that enrolled mixed- burden disease.
A common observation in many of these trials was a high incidence of brain relapse. In Tufts uni- versity study, the brain was the fi rst site of failure in 50% of recurrences, and the only site of recurrence in 36% of patients. The LCSG investigators noted that in patients who had complete resection, 28% of fi rst recurrence sites were in the brain, in contrast to only 7% in patients who did not undergo surgery. In pa- tients who experienced a recurrence in the brain, in almost one third that was the sole site of recurrence.
Similar fi ndings were noted by the SWOG 8805 study.
The CALGB protocol called for prophylactic cranial irradiation (PCI) in patients with non-squamous his- tologies who completed all the treatment, but about a third of eligible patients did not receive it. None of 13 patients who received PCI developed brain me- tastases, compared to one out of seven who were eli- gible but did not receive it. In SWOG 8805, PCI was optional, and there was no signifi cant difference in
rates of brain recurrence in the irradiated subset, al- though numbers were too small to reach a defi nitive conclusion about this issues.
The Tufts trial utilized a higher dose of preopera- tive RT, a prescription similar to those used for stan- dard concurrent chemoRT without surgery. Thus most of the allowable dose of RT was given upfront without a break. In the other trials, truncation of the RT occurred at around 45–50 Gy to plan for the surgery. Thus, patients with residual disease or un- resectable disease could only receive full dose RT via an interruption of several to many weeks, depending on time to recovery from surgery. However, a high dose of RT in the preoperative setting results in in- creased fi brosis that may increase the risk of surgical complications (as will be discussed later), so it can- not be universally recommended without additional prospective study.
3.2.2.3.3
Long-Term Survival in the Second-Generation Induction Trials
Long-term outcomes of selected second-generation studies with a minimum of three years of follow-up are summarized in Table 3.2.2.7. The direct compar- ison of outcomes between those studies is impos- sible due to differences in methodology and patient populations entered on these trials. Nevertheless, the long-term outcomes were encouraging and provided support for subsequent phase III trials.
Table 3.2.2.6. Results of second-generation trials of induction chemoradiotherapy in NSCLC
Investigators Response
rate (%)a
Complete resection rate (%)a
Treatment- related mortality (%)a
Operative mortality (%)b
pCR (%)a
PCR in N2 (%)a
Median survival (months) SWOG 8805
(Albain et al. 1995)
59 71 10 8 15 38 15
LCSG 852
(Weiden and Piantadosi 1992)
56 52 8 7 9 Not stated 13
Rush-Presbyterian (Faber et al. 1989)
92a 71 3.5 5 20 26 22
CALGB I
(Strauss et al. 1992)
64c 61 15 10 17 Not stated 16
Tufts
(Vora et al. 2000)
69a 79 0 0 21 59 30
SWOG, Southwest Oncology Group; LCSG, Lung Cancer Study Group; CALGB, Cancer and Leukemia Group B.
a Percentage of the original number.
b Percentage of patients subjected to surgery.
c Includes stable disease.
3.2.2.4
Third-Generation Phase II Studies of Induction Chemotherapy plus Concurrent Hyperfractionated Radiotherapy
Three phase II trials were conducted with an induc- tion regimen that consisted of platinum-based che- motherapy and hyperfractionated radiotherapy. In one of these trials, the radiation schedule included
a planned break, while in the other two, the radia- tion was intensifi ed by delivering it in an accelerated fashion. The designs of the trials are summarized in the Table 3.2.2.8. The MGH study enrolled 42 patients to a preoperative regimen consisting of split course, hyperfractionated radiotherapy concurrent with che- motherapy (Choi et al. 1997). All patients had N2 disease confi rmed histologically prior to treatment.
Thirty three percent of patients enrolled on this study
Table 3.2.2.7. Long-term survival in selected second-generation phase II induction trials in NSCLC
Investigators Disease
burden
Included T3N0 or N1?
Biopsy proof of N2 status required?
Selected stage IIIB included?
Long-term survival
Memorial
(Martini et al. 1993)
Mixed volume
No Yes No 28%, 3-year;
17%, 5-year Toronto
(Burkes et al. 1992)
Mixed volume
No Yes No 26%, 3-year
SWOG 8805
(Albain et al. 1995, 1999) High volume
No Yes Yes 27%, 3-year, 20%, 6-year, stage IIIA (N2);
24%, 3-year, 22%, 6-year, stage IIIB CALGB I
(Strauss et al. 1992)
High volume
Yes No No 28%, 3-year
22%, 7(+)-year CALGB 8935
(Sugarbaker et al. 1995) High volume
No Yes No 23%, 3-year
Rush-Presbyterian (Faber et al. 1989)
Mixed volume
Yes No Yes 40%, 3-year
Tufts
(Vora et al. 2000)
High volume
Yes No Yes 37% 5-year
CR, complete response; SWOG, Southwest Oncology Group: CALGB, Cancer and Leukemia Group B.
Table 3.2.2.8. Third-generation phase II trials of concurrent induction chemoradiotherapy with hyperfractionation in NSCLC Investigators Stage subset(s)/number of
patients
Disease burden
Chemotherapy Radiotherapy
MGH
(Choi et al. 1997)
Biopsy-proven stage IIIA(N2), n=42
Mixed volume
PVF × 2 concurrent with RT
→ surgery → PVF × 1 concurrent with RT
42 Gy split (1.5 bid × 7 → 10 day rest → 1.5 bid × 7); postopera- tive 12–18 Gy 1.5 bid) West German
Cancer Center (WGCC) (Eberhardt et al. 1998)
Mediastinoscopy required:
– 6, advanced T3 N0/1;
– 46, 2 or more N2 nodes;
– 42, IIIB (T4) or contralateral N3) Total n = 94
High volume
EP × 3 → reduced dose EP × 1 with RT
→ surgery
45 Gy (1.5 Gy bid over 3 weeks); PCI later in trial
German Lung Cancer Cooperative Group (GLCCG) (Thomas et al. 1999)
– N2, 25; (all biopsy-proven) – T4 or N3, 29;
Total n=54
High volume
ICE x 2 → PVd × 1 + RT → surgery
45 Gy (1.5 Gy bid over 3 weeks)
MGH, Massachusetts General Hospital; n, number of patients; P, cisplatin: V, vinblastine; F, 5-fl uorouracil; E, etoposide; I, ifosfamide, C, carboplatin; Vd, vindesine; Gy, gray; PCI, prophylactic cranial irradiation.
had mediastinal lymph nodes smaller than 1 cm on a pretreatment CT, and in 19 % the lymph nodes were greater than 2 cm. The volume of mediastinal disease was thus mixed in this study. Twelve Gy of postoperative RT was given for either complete re- sponse or microscopic disease only, and 18 Gy for residual disease or positive margins, concurrent with chemotherapy.
The West German Cancer Center study used 3 cycles of induction chemotherapy, followed by con- tinuous hyperfractionated accelerated RT concurrent with chemotherapy (Eberhardt et al. 1998). Patients eligible for enrollment had to have either surgically unresectable disease, or more than 1 ipsilateral medi- astinal lymph node involved, or positive contralateral mediastinal lymph nodes. This study mandated re- peat mediastinoscopy at the completion of induction treatment. Only those patients whose mediastinal tu- mor burden was downstaged (defi ned as a negative mediastinal biopsy or only one positive lymph node) were offered surgical resection. Thus, all patients with stable disease were not mandated to proceed to tho- racotomy. Patients who did not undergo resection of residual disease were given additional RT to a total of 60 Gy. These investigators reported a high incidence of isolated brain relapse and introduced prophylac- tic cranial irradiation (PCI) in the third year of the study. The PCI dose was 30 Gy in 2 Gy fractions over
3 weeks starting 1 day after the last chemotherapy administration.
The German Lung Cancer Cooperative Group trial accrued 54 patients to a regimen that consisted of 2 cycles of induction chemotherapy, followed by hyper- fractionated accelerated RT concurrent with chemo- therapy, followed by resection (Thomas et al. 1999).
Eligibility criteria included either biopsy-proven N2 disease or clinical T4 or N3 disease. Patients who had a tumor response or stable disease were eligible for surgery. Patients who did not have complete resec- tion received additional 16 Gy of radiotherapy.
The results of these trials are presented in the Table 3.2.2.9. Treatment-related mortality was 7%, 6% and 9% and postoperative mortality 5%, 7% and 8% (of patients who underwent thoracotomy) in the MGH, WGCC and GLCCG trials, respectively. The main perioperative complication seen in both WGCC and GLCCG trials was bronchial stump insuffi ciency, most often after right-sided resections. Both groups started reinforcing bronchial stumps with tissue later in each trial, reducing the incidence of this problem to zero.
A complete resection with negative margins was accomplished in 81% of all patients in the MGH trial.
The median survival was 25 months and overall sur- vival was 66%, 37% and 37% at 2, 3 and 5 years, re- spectively. The preoperative size of mediastinal nodes (<= 1 cm vs >1 cm) did not infl uence the survival,
Table 3.2.2.9. Results from third-generation trials of induction chemoradiotherapy with hyperfractionation in NSCLC
Investigators Number
of patients
Resection rate (%)a
Treatment related deaths (%)a
Postoperative deaths (%)b
Survival Predictors of favorable outcome
MGH
(Choi et al. 1997)
42 93% 7 5 37%, 5-year • Downstaging to N0
(79% 5-year survival)
• Complete resection West German
Cancer Center (WGCC) (Eberhardt et al. 1998)
94 53%a
(60% IIIA, 45% (IIIB)
6 7 28%, 4-year
(31% IIIA 26% IIIB)
4-year survival from registration:
• complete resectionc 46% vs 11%, p=0.0001
• N2/3 → N0 38% vs 15%, p=0.11
• LDH 240 or not 37% vs 0%, p=0.003
• PCI Decrease in fi rst brain metastases, p=0.005 German Lung Cancer
Cooperative Group (GLCCG)
(Thomas et al. 1999)
54 63% (R0) 9 8 30%, 3-year • > 90% histological regression (3-year survival 48% vs. 9%, p=0.007)
• Complete resection (p=0.009) MGH, Massachusetts General Hospital; CR, complete response; p, pathologic; PCI, prophylactic cranial irradiation.
a Percentage of the original number of patients.
b Percentage of patients subjected to surgery.
c Resection not mandated if persistent T4 or N2/N3 disease.
but the sample size was very small. Four patients had pCR, three of whom showed only a partial response on postinduction CT. Five-year survival was 79% if the nodes were downstaged to N0.
Of patients entered on the West German Cancer Center study, 64% were eligible for surgery after the induction regimen and 53% had complete re- section with negative margins. Twenty-four (26%) had complete pathological response. Among 29 pa- tients with radiographically stable disease after the induction treatment, about a third was completely resected and three had pathological complete re- sponse. Median survival was 20 and 18 months and 3-year survival were 36% and 31 % for stages IIIA and IIIB, respectively (no statistical difference).
No differences were observed for the different TNM categories and T (T1/2 vs. T3/4) and N (N0/1 vs. N2/3) subgroups. The complete resection rates were 60% for IIIA and 45% for IIIB. Of 8 patients with T4N0-1, 6 were able to have a complete re- section. Prophylactic cranial irradiation markedly reduced the incidence of brain relapse, but the dif- ference in median survival (26 months with PCI and 20 months without) did not reach statistical significance, possibly because the follow-up period for the first group was shorter.
A complete resection with negative margins was achieved in 63% of patients enrolled on the GLCCG trial. Over a half of these exhibited a major histologi- cal response, defi ned as necrosis or fi brosis of more than 90 % of tumor cells. Seven (13%) had pathologi- cal complete response. Preoperative assessment of response (complete/partial) did not correlate with the degree of tumor regression. Approximately 25%
of patients who relapsed had only a local recurrence, whereas 35% had a distant-only relapse. The median survival for the whole group was 20 months, with 2- and 3-year survival 40% and 30%, respectively.
Median survivals for stages IIIA and IIIB (25 vs. 17 months) showed no statistical signifi cance, as did 2- and 3-year survivals (52% and 35% vs. 30 and 26%).
The MGH study had higher resection rate and overall survival than the two German studies but also enrolled patients with less advanced disease. The two German trials had similar patient populations, treatment and outcome. The authors of those studies credit the accelerated radiation schedule for the fact that many of their patients with advanced, high-vol- ume disease were able to undergo resection. However, second-generation trials with concurrent chemoRT in patients with high-volume tumor burdens (de- scribed above, e.g., SWOG 8805) also achieved high resection rates.
3.2.2.5
Predictors of Favorable Outcome in Second- and Third-Generation Phase II Studies
Several of the phase II studies discussed above also reported prognostic factors, although many of the studies were underpowered for robust statistical anal- yses. These trials are summarized in Table 3.2.2.10.
Favorable factors included postinduction pathologi- cal complete response, complete resection, T3N0 and T3N1 disease, T4N0 or T4N1 disease and pathological clearance of the initial mediastinal nodal involve- ment. Not all of these factors were assessed in each study.
The only factor predictive of intermediate survival (2-3 years) in the SWOG 8805 trial was pathologi- cal clearance of nodal disease (Albain et al. 1995).
Complete resection rate, pathological complete re- sponse and multiple other factors did not reach sta- tistical signifi cance. However, complete resection later emerged as a predictor of long-term (six-year) survival, along with nodal pathological clearance (Albain et al. 1999). The six -year survival was 33%
in patients with pathological complete response in the nodes, compared to 11% for those who did not have the pathological nodal clearance. The 6-year survival for complete resection yes vs no was 29%
and 0%, respectively. The Tufts, MGH and WGCC trials also found mediastinal downstaging to be of prognostic importance. SWOG 8805 was the only second-generation induction study that assessed the nodal downstaging in a multivariate model.
Clinical response to neoadjuvant therapy in most of the trials did not correlate with the degree of tu- mor regression on pathology. However, clinical re- sponse to treatment was a favorable outcome predic- tor in the Memorial and WGCC trials. Pathological complete response or major regression (only micro- scopic residual disease) was an important predictor for survival in the Memorial, Tufts and GLCCG trials.
In the WGCC study, tumor persistence in the resected specimen was not associated with adverse prognosis, but all patients with stable disease did not undergo a resection in this trial.
Metastatic disease remains the most diffi cult ther-
apeutic problem in NSCLC, so it is critical to iden-
tify predictors of which patients will benefi t from a
surgical resection. Mediastinal downstaging may be
a marker of chemosensitivity of the metastatic clones
of tumor cells. This theory may explain why medi-
astinal downstaging, but not pathological complete
response in the primary tumor, carries a prognostic
signifi cance. Conversely, the presence of persistent
disease in the mediastinum may indicate unrespon- sive distant disease. Whether this marker can be reli- ably assessed without major morbidity, and if so, can it be used in selecting patients who might derive the most benefi t from surgical resection is uncertain.
Second look mediastinoscopy is technically diffi cult.
Molecular markers, such as p53 or K-ras, as well as more recently-described gene expression profi les, on specimens obtained pre-and post-induction treat- ment, are being studied as ancillary projects within several of these trials and other ongoing studies. Also, investigations regarding the role of PET scan “re- sponse” in the mediastinal nodes are underway on a large and prospective scale, based upon encouraging results in small pilot studies. However, PET scanning may not be sensitive enough to detect residual nodal microscopic disease.
3.2.2.6
The Stage IIIB Subset in Induction Trials
Although several of the second-generation trials (LCSG 852 and the Rush Presbyterian study) allowed the inclusion of the IIIB subset, the sample sizes were too small to allow for independent statistical analysis.
The SWOG 8805 study was designed to include a
suffi cient sample of the stage IIIB subgroup to allow independent assessment of outcome (Albain et al.
1995). Six-year survival for T4N0-1 was 49% versus 20% for the IIIA(N2) subset and 18% for T4N2 or TanyN3 (Albain et al. 1999). These long-term sur- vival data are a major improvement over results from trials of chemoRT without surgery in any stage III subset. Another intriguing stage IIIB subset result from SWOG 8805 pertained to N3 disease. Among patients with contralateral mediastinal (N3) involve- ment no one survived 2 years, whereas 35% of pa- tients with N3 disease due to supraclavicular involve- ment survived at least 2 years.
The Tufts University trial also reported IIIB group separately, but unlike SWOG 8805, pathological deter- mination of IIIB status was not required (Vora et al.
2000). Nevertheless, the Tufts investigators also noted excellent survival among patients with resected T4N0 tumors at initial staging, with a median survival of 51 months. The resection rates were 76% and 76%
for stage IIIA, and 63% and 50% for stage IIIB in the Tufts and SWOG trials, respectively.
The two- and three-year survivals in the SWOG 8805 trial were identical for stage IIIA(N2) and IIIB subsets (Albain et al. 1995, 1999). Similar observa- tions were made in the West German Cancer Center and the German Lung Cancer Cooperative Group studies (Eberhardt et al. 1998; Thomas et al. 1999).
Table 3.2.2.10. Predictors of favorable outcome in trials of induction therapy
Study Group Favorable outcome predictors
Memorial
(Martini et al. 1993)
• Major response to chemotherapy (5-year OS 19% vs. 7%)
• Complete resection (5-year OS 27% vs. 12%)
• Complete pathological response (5-year survival 61%) SWOG 8805
(Albain et al. 1995, 1999)
• Pathological mediastinal clearance (3-year survival 44% vs. 18%, p=0.05)
• Complete resection CALGB 8935
(Sugarbaker et al. 1995; Kumar et al. 1996)
• Complete resection (3-year survival 46% for complete resection vs. 23%
for incomplete resection vs. 0 for non-resected) Tufts
(Vora et al. 2000)
• Complete resection
• Complete pathological response
• Mediastinal clearance Rush-Presbyterian
(Faber et al. 1989; Reddy et al. 1992)
• Resection (3-year OS 47% vs. 17%, p=0.0001)
• Pathological complete response MGH
(Choi et al. 1997)
• Pathological nodal clearance (p=0.04)
• Complete resection (p=0.02) WGCC
(Eberhardt et al. 1998)
• Clinical response
• Complete resection (median survival 42 vs. 13 months, p=0.0001)
• Pathological nodal downstaging GLCCG
(Thomas et al. 1999)
• Pathological tumor regression >90% (3-year survival, 56% vs. 9%,
• Complete resection (p=0.009) OS, overall survival.
In the WGCC trial, 4-year survival was 31% and 26%
in stages IIIA and IIIB, respectively (p=0.59). In the GLCCG, 3-year survival was 35% and 26%, for stages IIIA and IIIB (p=0.33).
Grunenwald et al. (2001) prospectively studied 40 patients with IIIB disease, of whom 30 had T4 dis- ease and 18, N3. Five patients had T4N0 tumors and one had T4N1. Eligible patients had disease judged to be potentially resectable after a course of preop- erative therapy. All patients underwent pretreatment surgical staging. Induction treatment consisted of 5- FU, cisplatin and vinblastine for 2 cycles. A total of 42 Gy of external radiotherapy was given split in two 21 Gy courses, 1.5 Gy BID, with 10 days of rest between the courses. Radiotherapy began on the fi rst day of chemotherapy. Response was assessed a month after completion of all therapy. Patients who responded to the induction regimen underwent thoracotomy. A clinical response was obtained in 73% of patients and in 60% resection was performed. The resection was complete in all but one patient who underwent thora- cotomy. Four patients (10%) had complete pathologi- cal response. Of the patients with N2 or N3 disease, 30% had complete mediastinal clearance. There were 5 treatment-related deaths and 7 additional patients suffered serious morbidity. Median survival was 15 months and fi ve-year overall survival was 19%. Thirty percent of overall patient number had locoregional relapse and 50% had distant relapse. Pathological me- diastinal nodal downstaging was the only signifi cant favorable prognostic factor in a multivariate analysis (5-year survival 42% for post-induction N0/1 vs. 12
% for postinduction N2/3 for resected patients). All long-term survivors had persistent viable tumor cells in the primary tumor but 6 of 7 were postinduction N0-1.
Pitz et al. (2002) treated patients with stage IIIB NSCLC with neoadjuvant gemcitabine and cisplatin, followed by surgery in responding patients. No pre- operative RT was given. Twelve of the patients had T4N0 tumors, 21 had T1-3N3 and the remaining had T4N2 disease. Patients with supraclavicular lymph node involvement were excluded from the protocol. A repeat mediastinoscopy was required however it was possible to complete in only a fraction of patients, and was falsely negative in some. Patients received post- operative radiotherapy for persistent nodal involve- ment, positive margins or incomplete resection. The investigators reported a response rate of 66%, resec- tion rate of 44% and perioperative mortality of 2.4%.
Median survival for all patients was 15.1 months and 3-year survival was 15%. The investigators found no difference in outcome between T4N0 and N2/N3 sub-
sets. However, only patients with a response after in- duction chemotherapy were considered for surgical resection.
Collectively, these trials support the feasibility of induction therapy in stage IIIB NSCLC, and under- score the potential importance of resection of both responding and stable disease. They highlight the T4N0/1 substage as a group that does particularly well with trimodality therapy.
3.2.2.7
Patterns of Failure in Second- and
Third-Generation Phase II Induction Trials Patterns of failure were reported in most trials, either as a percentage of the entire number of patients or as a percentage of patients with resected disease, as summarized in Table 3.2.2.11. The preponderance of relapses is distant, especially among patients who un- derwent resection, however the number of locore- gional relapses is not insignifi cant.
All patients who experienced a local-only failure in the Memorial study had an incomplete resection.
The patterns of failure in the Rush-Presbyterian and SWOG trials were unaffected by nodal downstag- ing. In studies that analyzed the patterns of failure between patients with resected and unresected dis- ease separately, locoregional failures occurred less frequently in those patients who had a complete re- section.
A high incidence of brain relapse was noted uni- versally across these trials. For many patients, this was the only site of relapse. In the Dana Farber and CALGB 8935 studies, 15 % and 41% of fi rst relapses occurred in the brain, respectively. In LCSG 852 trial, 28% of initial recurrences among patients with a complete resection occurred in the brain, compared with 7% among patients with no or incomplete resec- tion.
3.2.2.8
Randomized Trials of Surgery Alone Vs Induction Therapy Followed by Surgery in Resectable IIIA NSCLC
The trials included in this section generally involved
patients with low bulk or minimal N2 disease. The
control arm in these studies was surgery alone. The
experimental arm used induction chemotherapy
with or without RT. The design of these studies is presented in Table 3.2.2.12.
Patients with a higher-volume disease burden were enrolled in the NCI (multiple N2 nodes on me- diastinoscopy) and the Japanese (clinically bulky) trials. (Pass et al. 1992; Yoneda et al. 1995) The NCI study had the most homogenous population since it required histological documentation of N2 dis- ease and excluded N3 disease. However, only 28 pa- tients were accrued and the trial closed prematurely.
Radiotherapy (54-60 Gy) was given postoperatively in non-chemotherapy arm, but not in chemotherapy arm. The pattern of failure in the surgery-RT arm was predominantly distant (>90%), while in chemo- therapy-surgery arm was about 67% locoregional and 33% distant. The results of this very small trial were nevertheless provocative regarding the poten- tial benefi t of induction chemotherapy in resectable disease.
Two frequently discussed trials of preoperative chemotherapy in patients with early stage III dis-
ease were conducted by the investigators from the MD Anderson Cancer Center and Spain (Roth et al.
1994, 1998; Rosell et al. 1994). The accrual to each of these trials was a halted at 60 patients per trial because of early emergence of increased survival in the induction chemotherapy arm. The Spanish trial was critiqued because of the very poor survival in the control group (8 months median survival, with no patient surviving 2 years), more consistent with that of stage IV patients treated with chemotherapy.
The MD Anderson trial was updated in 1998 (Roth et al. 1998). The advantage of the perioperative chemo- therapy arm was maintained, although the statistical signifi cance became borderline (p=0.056, log-rank test; p=0.048, Breslow-Gehan-Wilcoxon test).
The French Thoracic Cooperative Group Trial en- rolled patient with stage IB to IIIA disease (Depierre et al. 2002). All patients were judged to have resectable disease before any induction treatment. Staging was clinical (radiographic) and pre-surgery mediastinos- copy was not required. An excess of patients with N2
Table 3.2.2.11. Patterns of failure in second- and third-generation phase II trials Investigators Disease burden Local or
locoregional only failure (%)
Combined local-and distant failure (%)
Distant-only failure (%)
Denominator
Dana-Farber III (Elias et al. 1997)
Mixed volume 30 22 48 All patients
CALGB I
(Strauss et al. 1992)
Mixed volume 36 18 36 All patients
MGH
(Choi et al. 1997)
Mixed volume 15 10 75 All patients
SWOG 8805 (Albain et al. 1995)
High volume 11 28 61 All patients
GLCCG
(Thomas et al. 1999)
High volume 25 41 34 All patients
Rush-Presbyterian (Faber et al. 1989;
Reddy et al. 1992)
Mixed volume 26 18 56 All patients
Toronto
(Burkes et al. 1992)
Mixed volume 25 13 62 Resected patients only
Memorial
(Martini et al. 1993)
Mixed volume 26 0 74 Resected patients only
LCSG 852a
(Weiden et al. 1992)
High volume 33 0
11 17
50 67
All patients
Resected patients only CALGB 8935
(Sugarbaker et al. 1995;
Kumar et al. 1996)
High volume 25 4
44 39
31 57
All patients
Resected patients only
WGCC
(Eberhardt et al. 1998)
High volume 43 22
11 6
46 72
All patients
Resected patients only
a Does not include four cases of second primary tumor.
disease was accrued to the chemotherapy arm (12%), but the difference was not statistically signifi cant (p=0.065). Complete resection rate was 92% in the in- duction chemotherapy arm, and 86% in surgery alone arm. Postoperative radiotherapy to 60 Gy was deliv- ered for pathologic T3 or N2 status, or if the resection was incomplete. Forty-one percent of patients in sur- gery alone arm and 23% in induction chemotherapy arm received postoperative RT. The 1-, 2-, 3- and 4- year survivals were 77%, 71%, 59% and 44%, respec- tively, in the induction chemotherapy arm and 73%, 52%, 41% and 35% in the surgery alone arm. The dif- ference did not reach statistical signifi cance (p=0.15).
Stage-adjusted relative risk of death was 0.80 in the chemotherapy arm (p=0.089). In a subset analysis, there was a benefi t to induction for patients with N0- 1 disease (RR 0.68, p=0.027), but not for patients with N2 (RR 1.04, p=0.85). There was excess risk of deaths within the fi rst 5 months after the surgery in the in- duction chemotherapy arm (RR 1.32, p=0.37), but the curves crossed at 5 months and the RR in the induc- tion chemotherapy arm decreased to 0.74 after these fi rst 5 months. There was a non-signifi cant excess of mortality (10% vs. 5%) in the induction chemother- apy arm, consisting of pneumonia, empyema, fi stula and pulmonary embolism. Induction chemotherapy reduced the risk of distant relapse (RR=0.54, p=0.01).
Locoregional relapses were not signifi cantly different between the treatment arms.
The MD Anderson and Spanish studies are of- ten quoted in support of induction chemotherapy in early, low-volume stage III NSCLC. Their results are indeed provocative, but both of these studies had very small numbers of patients so that even a minor imbalance in prognostic factors between the two arms could have resulted in a major difference on the outcome. There was an excess of tumors with K-ras mutation and aneuploidy in the control arm of the Spanish study, a factor associated with an adverse prognosis. In the MD Anderson trial, there were more T4 tumors in the surgery alone arm, although this difference was not statistically different. Thus, the encouraging results of these trials must be confi rmed in larger phase III trials conducted in homogenously staged and treated patient populations.
3.2.2.9
Radiotherapy as a Component of the Induction Regimen
Radiotherapy hypothetically plays an important role in patients with locally advanced tumors in increasing
Table 3.2.2.12. Reported phase III trials of surgery with or without induction therapy in resectable NSCLC
2–3 Year survival Investigators Stage subset(s) Disease
burden
Chemotherapy Radiotherapy Patient No.
No
ChT ChT p Value NCI
(Pass et al. 1992)
IIIA(N2) by biopsy High volume
EP 2 cycles preop EP 4 cycles postop
Postoperative in no-ChT arm only (54–60 Gy)
28 21% 46% 0.12
Japan (Yoneda et al.
1995)
Clinical IIIA and IIIB
High volume
VdP pre- operative
Concurrent with CT
83 40% 37% NS
M.D. Anderson (Roth et al.
1994, 1998)
IIIA(N2) not required;
node biopsy not required; some IIIB
Low volume
CEP pre- and postoperative
Postoperative only if residual disease
60 15% 56% <0.05
Spain (Rosell et al.
1994)
IIIA(N2) not required;
node biopsy not required
Low volume
PIM preoperative Postoperative for both arms
60 0% 30% <0.05
French Thoracic Cooperative Group (Depierre et al. 2002)
Clinical T2N0, II, IIIA Low volume
MIP × 2 pre- operative; also postoperative, if objective response
Postoperative to 60 Gy, if pT3 or pN2 for both arms
355 41%a 52%a p = 0.15b
E, etoposide; P, cisplatin; V, vinblastine; I, ifosfamide; Vd, vindesine; M, mitomycin, C; C, cyclophosphamide; NS, not signifi - cant; NCI, National Cancer Institute; ChT, chemotherapy.
a In N0-1 disease p=0.027, in N2 disease p=0.85.
b 3-Year survival.
rates of downstaging and resectability. Radiotherapy may also be benefi cial, either preoperatively or post- operatively, in sterilizing microscopic mediastinal disease that cannot be completely removed during the surgery. In patients with microscopic N2 disease who have disease that is resectable upfront, the role of RT is much less certain.
Despite this, the utility of RT in neoadjuvant regi- mens in high-volume disease has been questioned.
The only randomized trial to date that addressed the necessity of radiotherapy in the induction regimen was that of Fleck et al., conducted in Brazil and reported only in abstract format (Fleck et al. 1994). The inves- tigators randomized 96 patients between induction MVP therapy followed by surgery or to cisplatin/5-FU concurrent with RT followed by surgery. Patients en- tered on the trial had largely advanced, high volume stage III NSCLC. The 5-year survival was improved in chemoradiotherapy arm, 31% vs. 15%, p=0.05. While the MVP regimen was commonly used at the time the study was conducted, mitomycin-C has been avoided in more recent trials due to its association with high rates of pulmonary complications. The 5-year survival in the MVP-surgery arm was very similar to the re- sults obtained with induction chemotherapy followed by defi nitive radiotherapy (Dillman et al. 1996).
A radiotherapy dose prescription of 40-45 Gy is favored in most induction regimens because it is effi cacious but does not result in excessive periop- erative and postoperative morbidity. Trials that used higher doses of RT had greater rates of postoperative complications, especially in association with pneu- monectomy (Fowler et al. 1993; Yashar et al. 1992;
Deutsch et al. 1994). One exception is the Tufts study that did not report any deaths after a neoadju- vant regimen that included 59.4 Gy of radiotherapy (Vora et al. 2000).
The optimal sequence of radiotherapy relative to surgery is also an unresolved issue. In patients with large, locally-advanced tumors, preoperative radiotherapy will likely improve respectability and may synergize with chemotherapy. Also, there is more certainty that the patient will receive the entire planned dose when the RT is given within the induc- tion treatment plan. The advantage of postoperative radiotherapy is that it can be given to a higher dose, which may be important in patients for whom a com- plete resection is not possible. One of the shortcom- ings of most induction chemoRT protocols is that eligibility for surgical resection practically must be determined before fi brosis sets in, usually 3-4 weeks after the completion of the induction with lower- dose RT. Those patients who cannot have surgery but
still have localized disease are then usually treated with additional RT after the protocol-induced break.
This may prevent achievement of the optimal benefi t from RT, since treatment breaks during radiotherapy have been associated with decrease in survival (Cox et al. 1993; Jeremic et al. 2003). However, postopera- tive RT programs often report poor compliance and many patients do not receive the planned therapy (Sugarbaker et al. 1995).
The schedule of radiotherapy in trimodality pro- grams also remains undefi ned. The hyperfractionated accelerated schedule intensifi es the effect of RT, which may be important in locally advanced tumors. This schedule was tolerated well and was not associated with excessive rate of perioperative complications in 3 pro- spective phase II trials (Choi et al. 1997; Eberhardt et al. 1998; Thomas et al. 1999). A recently completed phase III German trial built upon the phase II results and when completely analyzed, it will shed light on the role of RT in the induction versus postoperative RT (Thomas et al. 2004). This trial randomized patients with stage IIIA disease to preoperative induction che- motherapy followed by hyperfractionated accelerated RT plus chemotherapy, then surgery versus preopera- tive chemotherapy followed by surgery followed by standard fractionation postoperative RT. Since both of the arms included RT, this trial does not test whether RT is necessary for improved survival. However, it will provide important information on the impact of RT on the pathologic response rate, nodal downstaging, morbidity and resectability. It will address the ques- tion of whether nodal downstaging is in and of itself an important predictor of long-term survival.
3.2.2.10
Phase III Trials of Chemoradiotherapy With or Without Surgery
Several prospective, randomized trials involving tri- modality therapy were conducted in stage III NSCLC.
These trials asked different questions, and all but one closed early without reaching the planned accrual target. They are summarized in Table 3.2.2.13.
3.2.2.10.1
Induction Chemotherapy Followed by Surgery vs Radiotherapy Alone
A small NCI Canada study randomized 31 patients to
RT alone versus induction cisplatin and vinblastine
chemotherapy followed by and surgery (Shepherd et al. 1998). The study was halted after a CALGB ran- domized trial showed the superiority of combined chemoRT over RT alone as defi nitive treatment of stage III NSCLC (Dillman et al. 1996). The RT-alone alone arm was no longer appropriate (suboptimal therapy). In the analysis of patients accrued up to that point, there was no difference in median sur- vival (16.2 vs. 18.7 months) or long-term survival (Shepherd et al. 1998).
3.2.2.10.2
Induction Chemotherapy vs Induction Radiotherapy
A CALGB trial randomized 57 patients with patho- logically documented N2 disease to induction RT to 40 Gy followed by surgery, followed by 14-20 Gy of additional RT vs. induction of 2 cycles of platinum/
vinblastine (PV) followed by surgery, followed by 2 more cycles of PV followed by RT to 54-60 Gy (Elias et al. 2002). There were only 2 pathological complete responses in the induction chemotherapy arm and none in the induction RT arm. Patients in the induc- tion radiotherapy arm experienced better local con- trol (76% vs. 50%, p=0.014). Less than half of patients
were able to complete the adjuvant portion of the chemotherapy. The trial was closed early due to poor accrual. There was no difference in survival between the arms (median 24 months in RT induction vs. 18 months in chemotherapy induction, p=0.46).
3.2.2.10.3
Induction ChemoRT Followed by Surgery vs Defi nitive ChemoRT Alone
Two studies have been conducted to date, one of which was terminated early and the other was com- pleted and recently reported.
The RTOG 8901 study accrued 73 patients to two treatment arms: induction chemotherapy with cis- platin, vinblastine, and mitomycin-C followed by surgical resection, versus the same chemotherapy followed by RT to 64 Gy (Johnstone et al. 2002).
Patients in both arms received consolidation cispla- tin and vinblastine chemotherapy. The original ac- crual goal was 244 patients, but the trial closed early due to poor accrual even though the protocol was amended to omit mitomycin-C after the fi rst 16 pa- tients. Pathologic documentation of N2 disease was required and the patients were stratifi ed by volume of disease. In all, 29 patients were randomized to sur-
Table 3.2.2.13. Reported phase III induction trials for NSCLC
Investigators Stage subset Question Study design Number of patients
Outcome comment
NCI Canada (Shepherd et al. 1998)
Biopsy-proven state IIIA(N2)
Postinduction surgery vs RT?
PV → Surgery vs
RT
31 Closed early due to radiotherapy alone arm; survival curves superimposed at 2 years RTOG 89-01
(Johnstone et al. 2002)
Biopsy-proven stage IIIA(N2)
Postinduction surgery vs RT?
MVP or VP Surgery vs RT MVP or VP
73 Closed early due to slow accrual;
p=0.62 for overall survival;
4-year: 22% for surgery vs 22% for RT
CALGB (Elias et al. 2002)
Biopsy-proven stage IIIA(N2)
Induction RT or chemo?
RT → Surgery → RT vs
PV → Surgery → PV → RT
57 Closed early due to slow accrual;
median survival 24 months (RT/S/RT) and 18 months (CT/S/CT) (p=0.4) INT 0139
(Albain et al. 2003)
Biopsy-proven IIIA (N2)
Postinduction surgery vs. chemo RT alone?
PE/RT → Surgery → PE vs
PE/RT → RT → PE
392 Preliminary results:
CT/RT/S CT/RT p 3-year OS 38% 33% 0.51 Med OS 22 mo. 21 mo.
3-year PFS 29% 19% 0.02 Med PFS 14 mo. 12 mo.
P, cisplatin; F, 5-fl uorouracil; M, mitomycin-C; V, vinblastine; E, Etoposide; RTOG, Radiation Therapy Oncology Group;
CALGB, Cancer and Leukemia Group B.
gery and 33 patients to RT. There was no difference in median survival (19.4 vs. 17.4 months) or in 1-, 2- or 4-year survival (70% vs. 66%, 48% vs. 34%, 22% vs.
22%, respectively).
The largest phase III trial to date that addresses the potential worth of surgery in stage IIIA(N2) NSCLC is the Intergroup 0139 trial, chaired by RTOG (Albain et al. 2003). The entry criteria for this study included T1-3 primary tumor, pathologically con- fi rmed N2 disease, feasible resection from a surgical standpoint and medical ability to undergo resection.
Patients were stratifi ed by performance status, T1–2 vs. T3, and whether contralateral mediastinal nodes required biopsy or not (mandated if nodes were vis- ible on CT scan), and randomized between the tri- modality versus the bimodality arm. The induction regimen was identical in both arms: 45 Gy of external radiotherapy given in a once daily fraction, concur- rent with day 1 of induction chemotherapy, which was cisplatin, 50 mg/m2 on days 1, 8, 29, 36 and eto- poside, 50 mg/m2 days 1–5 and 29–33. Patients were reevaluated by a CT scan 2–4 weeks after completion of the induction regimen in the surgical arm, and in the RT arm, a week before completion of treatment.
Those patients with no progression proceeded with their assigned treatment. In the surgical arm, the treatment consisted of resection of all known disease and mediastinal nodal sampling. In the RT arm, the radiotherapy continued to 61 Gy without a break. In both arms, consolidation chemotherapy (two cycles of cisplatin and etoposide) was given to all patients.
The study initially was designed to accrue 510 pa- tients, but the Data Safety and Monitoring Board rec- ommended closure with 429 accrued patients due to suffi cient events based on the slower than anticipated accrual.
The fi rst interim results were recently presented (Albain et al. 2003). At a median follow-up of 69 months, 392 patients were analyzable. Induction treatment was delivered as per the protocol equally in both arms. In the surgical arm, a thoracotomy was performed in 96% and a complete resection was ac- complished in 88% of patients for whom the data were available. There were 18% pathologic complete responses (T0N0) and 46% with pathologic nodal clearance. The chemoRT toxicity was similar in both arms, with the exception of esophagitis which was more common in the chemoRT arm. Consolidation chemotherapy was not administered to 42% of pa- tients undergoing surgery and 21% of those not having undergone surgery (p<0.001). Conversely, RT was delivered according to protocol in 81% on the chemoRT arm versus 97% on the surgery arm
(p=0.002). Three patients (1.6%) in chemoRT arm and 14 (7%) patients in chemoRT-surgery arm died from treatment-related toxicity. In the latter group, ten of these deaths were caused by postoperative complica- tions. Most of the deaths occurred in patients who underwent pneumonectomy (especially right-sided), and the most frequent cause of death was acute respi- ratory distress syndrome (ARDS).
Median progression-free survival was 14.0 months and 11.7 months in the chemoRT-surgery arm and chemoRT arm, respectively. Three-year progression free survival was 29% in the chemoRT-surgery arm vs. 19% in chemoRT arm (log rank p=0.02). The me- dian overall survival was 22.1 months versus. 21.7 months and the 3-year survival was 38% vs. 33% in the chemoRT-surgery and ChemoRT arms, respec- tively (log rank p=0.51). The overall survival curves cross over and begin to separate at 22 months. By 3 years, there was a 5% absolute survival benefi t in the surgical arm, but the confi dence intervals are wide and overlap. More patients died of treatment complications in the surgical arm, but more are alive without progression in the same treatment arm. Sites of relapse were also analyzed: 13% of patients in the chemoRT-surgery arm had locoregional relapse only versus 21% in the chemoRT arm (p=0.07). Relapse in the primary site was three times more common in the non-surgical arm. Brain was a common site of fi rst relapse in both arms (10% versus 18 % in the chemoRT and chemoRT-surgery arm, respectively, p=0.08).
Pretreatment factors predictive of favorable out- come were lower T stage, less than 5% weight loss and younger age. Female sex and normal LDH did not reach statistical signifi cance. After the induction treatment, patients who achieved complete response in the mediastinal nodes had median survival of 36.7 months and 3-year survival of about 50%, re- gardless of the response in the primary tumor.
3.2.2.11
Phase II Trials of Induction Regimens That Incorporated Third-Generation Chemotherapy Agents
Recent investigations tested third-generation che- motherapy agents within the induction therapy pre- scription. Selected studies with larger numbers of patients are presented below (see Table 3.2.2.14). One of the trials included patients with stages IB, II and
“early” IIIA, three studies enrolled patients with N2
biopsy-positive but resectable stage IIIA disease, and the last one included high-volume, advanced unre- sectable stage IIIA and IIIB disease. The diversity of patients prevents comparisons among studies as well as conclusions regarding an improvement over second-generation induction programs.
Preoperative carboplatin and paclitaxel chemo- therapy was tested by the BLOT group (Bi-modal- ity Lung Oncology Team) in 90 patients with stages IB, II, and selected IIIA NSCLC (Pisters et al. 2000).
Initially, 94 patients with stages IB through IIA (no N2) were administered two cycles (paclitaxel 225 mg/
m2 and carboplatin AUC 6) preoperatively and three postoperatively. The “major response” rate was 56%.
At the time of thoracotomy, 86% of the original num- ber of patients was able to undergo complete resec- tion. There were two deaths related to surgery and one related to induction therapy, for a total mortality of 3%. Pathologic complete response was observed in six patients (6%). Only 43% were able to receive the planned postoperative chemotherapy. After this initial analysis, the protocol was amended to three preoperative cycles of the same chemotherapy and 40 additional patients were accrued. The results were presented recently (Pisters et al. 2003). Five year- survival for the cohort receiving two cycles of pre- operative chemotherapy was 46%. The patients who received three cycles of preoperative therapy had
48% 3-year survival, but the follow-up was shorter.
The diversity of stages included in this trial precludes comparing the outcome of this trial to other studies.
It is uncertain whether these results represent a sur- vival improvement over second-generation induc- tion chemotherapy, but tolerance to treatment was extremely good.
The Swiss Group for Clinical Cancer Research (SAKK) enrolled patients with stage IIIA disease due to biopsy-proven ipsilateral mediastinal nodal involvement that were considered potentially oper- able (Betticher et al. 2003). The induction regimen consisted of cisplatin 40 mg/m2 on days 1–2 plus docetaxel 85 mg/m2 on day 1 for three cycles. All patients except those with progressive disease un- derwent thoracotomy. Postoperative RT to 60 Gy was administered for a positive resection margin and/or involvement of the uppermost mediastinal lymph node. Postoperative chemotherapy was not given. A total of 90 patients were enrolled, 18% of whom did not have mediastinal nodal enlargement on CT scan.
The protocol was later amended to increase the cis- platin dose to 100 mg/m2 per cycle.
The overall clinical response was 66%. Complete resection was accomplished in only 48% of the en- tire patient group. An additional 43% underwent incomplete resection with positive margins and/or positive highest mediastinal lymph node. It is of note
Table 3.2.2.14. Design and results of completed phase II trials using third-generation chemotherapy drugs within the induction regimen
Investigators Stage subset
Study design Patients
(n)
Response rate
Resection rate (R0)a
pCR Survival
BLOT (Pisters et al.
2000, 2003)
IB-IIIA (no N2)
TC × 2 → Surgery → TC x3 TC × 3 → Surgery → TC x3
94 40
56%
40%
86% 6% 3-Year 63%, 5-year 46%
3-year 48 % SAKK
(Bettincher et al. 2003)
IIIA (pN2), mixed bulk
PD × 3 → Surgery → variable RT 90 66% 48% 16% 3-Year 33%
De Marinis et al. (2003)
IIIA (pN2), bulky
GTP × 3 → Surgery→ variable RT 49 74% 55% 16% Median 23 months ILCP
(Capuzzo et al. 2003)
IIIA, IIIB (clin) bulky
GP × 4 → Surgery → variable RT 129 62% 29% 2% Median 19 months
EORTC
(Splinter et al. 2000;
van Zandwijk et al.
2000; O’Brien et al.
2003)
IIIA (pN2), bulky
GC → Surgery TC → Surgery
47 52
70%
64%
71%
80%
NR NR
T, paclitaxel; C, carboplatin; P, cisplatin; D, docetaxel; G, gemcitabine; NR, not reported.
a Of the original number of patients.
