Radiation /Chemo, then surgery ?

[z]

Hi,

I have so far gotten three different opinions from 3 different cancer centers on how to treat my particular cancer.

One is proposing radiation/chemo, then surgery, then chemo. So, I would like to ask - has any of you undergone such a treatment - surgery after radiation/chemo. If so, what were the circumstances and what was the experience?

Regards,

Z

[Ry]

I think what you describe is pretty much the common protocol. My husband did chemo and radiation hoping the tumor would shrink enough to be removed--it didn't. He then continued on with treatment since surgery wasn't an option. Studies have shown you have a better chance if you have chemo following surgery. Good luck to you.

[Jyoung20]

We were hoping for the same protocol. However, my onc told me that after radiation surgery wasn't really a posssibility because of the scar tissue left from the radiation. I really wish I would have known that was giong to happen.

Living life,

Jamie

[cindi o'h]

It is my understanding that in stage llla or earlier(?) that sometimes a tumor can be partially radiated for shrinkage, then surgery, then on to more radiation/ chemo.

To have the whole radiation completed leaves too much scar tissue which does not heal after surgery.

Time to get a balancing opinion to side with one of the 3 options that you have already had. Lucky to have OPTIONS! You are doing well to explore all of them!!! Keep it up. Try not to get discouraged. This in NOT easy! Keep doing your homework. Read. Understand. Knowledge is power. You can do this!

Cindi o'h

[Donna G]

That was my protocol. I had Cisplatin and VP16 with daily radiation from December til the first of February . Mid February I had my right upper lobe removed. After a couple of weeks of recovery from surgery chemo was resumed again til the first of April. After surgery I asked about the tumor and they said all of it was dead, scar tissue. The chemo after was to be sure to kill any posible mets. In other words it has been done for thousands of people. Best news I started this journey in December of 97 and this is September of 2005.

Best wishes for your treatment. Donna G

[z]

That is wonderful, I am glad it all worked out well for you.

I think the issue with mine is that the carinal lymphnodes are affected, which makes surgery more complicated.

Basically, the first opinion was to do just radiation and chemo, saying that curgery is not possible in my case. The second (John's Hopkins) wants to move on to full blown chemo, then surgery. Lombardi Center (Georgetown Univ., Washington, DC) proposes 40 g. of rediation with chemo, then surgery.

University of MD proposes I join this study, with full blown readiation with chemo, then surgery, then chemo... Here is the link for 0229 Phase II Lung

(Activation: 9/30/04) - http://rtog.org/members/active.html#lung

Regards,

Z

[Ry]

Just to address Jamie's comment above. If you have too many rads surgery is not possible because the area will not heal. You have to make it very clear to the radiation oncologist that surgery is a possiblility so they don't over radiate you.

[john]

Prior trials have established a benefit for adjuvant chemotherapy for (I think) patients with Stage Ib and greater disease. Pancoast tumors are another subset that seemed to do well with adjuvant chemo.

Neoadjuvant chemotherapy. Chemotherapy BEFORE surgery instead of after has not yet been proven statistically to be better than surgery alone.

There is one study below that shows a 12% or so better survival at 5 years. Though it is not

"statistically significant" because not enough people enrolled in the trial

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Non-Small Cell Lung Cancer

Neoadjuvant therapy for locally advanced non-small cell lung cancer has evolved rapidly near the turn of the century. Historically, radiation used to be the only treatment for unresectable non-small cell lung cancer. In 1990, Dillman et al[35] introduced the use of neoadjuvant cisplatin-based chemotherapy before radiation with better survival, and other chemotherapy regimens used in this fashion also yielded comparable results.[36-38] Nevertheless, adding adjuvant chemotherapy after radiation provided no additional benefit.[39,40] Subsequently, the use of neoadjuvant chemotherapy followed by radiation waned, when concurrent chemoradiation had been found to produce better survival outcome.[41] Today, concurrent chemoradiation is the standard of care for patients with unresectable non-small cell lung cancer who have good performance status.

In certain situations, concurrent chemoradiation has transformed its role from a definitive treatment into a neoadjuvant treatment before radical resection. Concurrent chemoradiation may render some unresectable non-small cell lung cancers resectable. Although no data from randomized, controlled trials are available, it is evident that patients with superior sulcus tumor or pancoast tumor, after undergoing neoadjuvant radiation with or without concurrent chemotherapy, may become eligible for complete resection and achieve prolonged disease-free survival.[42]

For patients with resectable but locally advanced non-small cell lung cancer, outcome of treatment with surgery alone is poor. Several small, randomized studies suggest that neoadjuvant chemotherapy before surgery improves overall survival when compared with surgery alone.[43-45] One such study, for instance, using 3 cycles of chemotherapy followed by surgery, demonstrated an increase in median survival from 8 months in the surgery-alone arm to 26 months in the neoadjuvant arm.[43] Subsequent larger studies, however, produced conflicting results.[46,47] Other investigators have experimented with concurrent chemoradiation followed by surgery in comparison with chemoradiation alone.[48] Preliminary data indicate that patients who respond well to chemoradiation may benefit from subsequent surgery, although long-term follow-up is still necessary.

Recently, Arriagada et al[49] have demonstrated a survival benefit of postoperative chemotherapy for resectable non-small cell lung cancer. To date, however, no large, randomized trials between neoadjuvant and adjuvant therapy is available, leaving the role of neoadjuvant therapy in resectable non-small cell lung cancer inconclusive.

-----------------------------------------------

Except:

Neoadjuvant cisplatin-based chemotherapy has already been shown to increase cure rates in stage IIIA NSCLC, from 10 to 15% to 25 to 30%. Newer active agents, such as paclitaxel, vinorelbine, and gemcitabine, may be able to advance the cure rate even further. Radiotherapy, which has been shown to decrease the rate of local recurrence, may play a role as well.

http://www.chestjournal.org/cgi/content ... ppl_1/119S

Meeting: 2005 ASCO Annual Meeting Bookmark

Category: Lung Cancer

SubCategory: Non-Small Cell Lung Cancer

A meta-analysis of neoadjuvant chemotherapy for resectable stage 1-3A non-small cell lung cancer

Abstract No: 7265

Author(s): Y. Huang, Y. Wu, X. Yang

Abstract: Background: Adjuvant chemotherapy has showed survival benefit for patients with early stage NSCLC in last two years. There were some clinical trials in evaluating the role of neoadjuvant chemotherapy for resectable stage 1-3A non-small cell lung cancer. The evidence was not enough to recommend as guideline in practice. Methods: Clinical control trials published between 1994 and 2004 on neoadjuvant chemotherapy for resectable NSCLC were included. Statistical analysis was performed using SPSS, including tests for homogeneity of studies and publication bias. Trials were analyzed by odds ratio (OR). Revman4.1 software was applied to process data. Results: Eight trials were included in meta analysis. A total of 1965 patients were included in the analysis (1001 cases in the neoadjuvant group and 964 in the surgery group). There was statistical significant difference in survival between the two groups. The odds ratio (OR) was 0.68 with 95% CI 0.56 to 0.83, p=0.0002). After further analysis, there was not statistical significant difference in survival in the higher quality trials (review scores >. The OR was 0.80 with 95% CI 0.58to 1.09, p=0.15). There was statistical significant difference in survival in the lower quality trials (review scores <. The OR was 0.62 with 95% CI 0.48 to 0.62, p=0.0002). Conclusions: It is not certain that neoadjuvant chemotherapy improved survival in patients with resectable stage 1-3A NSCLC. It is needed more RCT to answer this question

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Emerging Role of Adjuvant and Neoadjuvant Therapy in Early-Stage Non-Small-Cell Lung Cancer CME/CE

Disclosures

Chandra P. Belani, MD

Introduction

For the majority of patients, non-small-cell lung cancer (NSCLC) remains a lethal disease even when it is detected early. Treatment is dictated by the disease stage at which patients initially present; standard of care for early-stage disease depends upon whether the patient is a candidate for surgery. With surgical resection, the 5-year survival rate for patients with stage IB NSCLC is 57% and less than 50% for patients with stage II disease.[1] Although there have been major improvements in surgical techniques and postoperative care, the long-term outlook for patients has not changed significantly over the past few decades.

While local disease recurs in approximately one third of patients following surgical resection, distant disease is the primary cause of death for patients with early-stage NSCLC. Several studies have established the presence of micrometastasis at systemic sites in patients with early-stage NSCLC, with a corresponding trend toward inferior survival for those patients.[2,3]

Historically, attempts to improve postsurgical outcomes have focused on a variety of adjuvant therapies -- chemotherapy and/or radiation therapy -- aimed at eliminating disease recurrence and/or distant disease development.[4] Initial attempts did not yield much success, but a meta-analysis of 52 randomized adjuvant chemotherapy trials demonstrated a modest, nonsignificant 5% survival benefit for patients who received cisplatin-based chemotherapy following surgical resection[5]; this analysis formed the basis of new adjuvant trials with improved patient selection and more active drug regimens.

Adjuvant Therapy

Absolute improvements in survival ranging from 4.1% to 15% were reported with platinum-based adjuvant therapy for early-stage NSCLC in the International Adjuvant Lung Trial (IALT), Cancer and Leukemia Group B (CALGB), and National Cancer Institute of Canada (NCIC) JBR.10 trials during 2004.[6-8] These are landmark trials in the history of lung cancer treatment. Although the magnitude of benefit is not huge, it is significant (Tables 1 and 2).

Table 1. Landmark Adjuvant Therapy Trials

Author and Year Published # Pts Treatment Groups 5-Year Survival

% P Value

Arriagada et al[6] (IALT) 2004 1867 Cisplatin and either:

Etoposide

Vinorelbine

Vindesine

Vinblastine 44.5 < .03

OBS 40.4

Winton et al[7]

(JBR.10) 2004 482 Cisplatin-Vinorelbine 69 .03

OBS 54

Strauss et al[8]

(CALGB 9633) 2004 344 Carboplatin-Paclitaxel 71 (4 years) .028

OBS 59 (4 years)

Rosell et al[9]

(ANITA) 2005 840 Cisplatin-Vinorelbine 51 .0131

OBS 43

OBS = observation

The results of IALT, CALGB, and JBR.10 were confirmed by the successful ANITA (Adjuvant Navelbine International Trialist's Association) trial, presented at this meeting by Dr. Rafael Rosell.[9] The prospective phase 3 trial compared adjuvant cisplatin-vinorelbine (cisplatin 100 mg/m2 on day 1 every 4 weeks plus vinorelbine 30 mg/m2/week) with observation (OBS). A total of 840 patients with postoperative stage IB (T2N0), II, or IIIA NSCLC were enrolled from over 101 different centers in 14 countries. A 10% improvement in 2-year survival was the main end point of the trial; relapse-free survival was a secondary end point, as was toxicity analysis. There was a significant survival improvement with cisplatin-vinorelbine as adjuvant therapy compared with OBS-only following complete resection; at 70 months follow-up, median survival was 65.8 months with adjuvant chemotherapy vs 43.7 months without. Survival at 2/5/7 years was 68%/51%/45% in the adjuvant therapy arm compared with 63%/43%/37% for OBS. Five-year survival by stage I/II/IIIA was 62%/52%/42% in the adjuvant therapy arm compared with 63%/39%/26% for OBS. Grade 3/4 toxicities in the experimental arm were manageable: neutropenia 86%, febrile neutropenia 8.5%, nausea-vomiting 27%, constipation 5%, and peripheral neuropathy 3%. Five patient deaths were attributed to chemotherapy. Subset analysis of the ANITA trial demonstrated that significant improvement in survival was restricted to stage II and IIIA patients, and no benefit was observed in stage IB disease. The investigators recommend cisplatin-vinorelbine as standard of care after total resection for stages IIA, IIB, and IIIA.

Table 2. Adjuvant Therapy Trials Scorecard

Trial Stage IA Stage IB Stage II Stage IIIA

ALPI[10] Negative Negative Negative Negative

IALT[6] Negative Negative Negative Positive

NCIC[7] Not tested Negative Positive Not tested

CALGB[8] Not tested Positive Not tested Not tested

ANITA[9] Not tested Negative Positive Positive

New Information From Landmark Adjuvant Trials

The landmark study that established a confirmed survival benefit for adjuvant therapy is the IALT trial of 1867 patients originally reported by Arriagada et al in 2004.[6] At this meeting, Soria and colleagues[11] reported a planned subanalysis of tumor tissues (n=783) from the IALT study in an attempt to learn more about response and human telomerase reverse transcriptase (hTERT). Of 783 cases, 770 were evaluable for hTERT staining, which was positive in 52% of cases. Percentages correlated with histology (P = .0001) as follows: 57% of squamous cell carcinoma, 44% of adenocarcinoma, and 48% of others were positive for hTERT. H-TERT expression did not correlate with stage, nodal status, or performance status, and it did not predict for survival (P = .43) or response to chemotherapy (P = .51).

Winton and colleagues[12] published a full report on the Intergroup JBR.10 study this summer. The randomized trial of 482 patients without N2 disease compared cisplatin-vinorelbine with surgery alone. Five-year survival in the adjuvant therapy group remains at 69% compared with 54% in the surgery-alone arm (P = .04). Tsao and colleagues[13] also reported a subanalysis of JBR.10 at this meeting, in which they examined the significance of k-Ras mutations. Mutations were found in 26% (117) of 450 samples, and 88/117 were in patients with adenocarcinoma histology; k-Ras mutations appear to predict lack of survival benefit from chemotherapy. Of note, k-Ras mutations are also found to correlate with lack of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and also appear to be more prevalent among current or former smokers.[14-16] However, data on k-Ras mutations, smoking, and resistance to either chemotherapy or EGFR TKIs have to be confirmed in larger studies.

Proposed Adjuvant Study

Based on the successful Eastern Cooperative Oncology Group (ECOG) 4599 trial,[17] in which bevacizumab added to carboplatin-paclitaxel significantly prolonged survival from 10.2 months to 12.5 months among 878 previously untreated patients with advanced NSCLC, ECOG proposes a trial using the same regimen as adjuvant therapy for early-stage postsurgical patients (Figure 1). The details of the trial design are being discussed.

Figure 1. ECOG proposal for adjuvant therapy plus or minus bevacizumab in stages IB, II, and IIIA (N2 negative).

Neoadjuvant Therapy for Early-Stage NSCLC

Neoadjuvant chemotherapy, also known as preoperative or induction therapy, offers several potential advantages, including downstaging the tumor before surgery and thus increasing the chances of a complete (R0) resection, as well as providing an opportunity to evaluate in-vivo effects of chemotherapy in resected specimens. Several investigators reported preliminary results of neoadjuvant studies at this meeting.

Bepler and colleagues[18] studied neoadjuvant gemcitabine-pemetrexed in 23 resectable NSCLC patients. Among 15 evaluable patients, the nonplatinum doublet produced 1 complete response (CR) and 4 partial responses (PRs). Nine patients had stable disease (SD), with results pending in 7 patients, and 2 were not evaluable. Gemcitabine (1500 mg/m2) and pemetrexed (500 mg/m2) were administered on days 1, 15, 29, and 43; reimaging studies were performed between days 50-63, and surgery was performed between days 64-77. Two patients required dose reductions for grade > 3 toxicities, and 11/13 patients underwent complete resection. The data are preliminary, and long-term follow-up is required for determination of overall efficacy.

Esteban and colleagues[19] administered cisplatin-gemcitabine with or without vinorelbine as induction therapy in 128 patients with stage III NSCLC. Patients who were candidates for surgery and/or radiation were included. Interim results show a CR rate of 20% in the doublet group and a 25% CR rate in the triplet group. CRs and PRs together totaled 66% in the doublet arm and 65% in the triplet arm. The incidence of recurrence in the 2 groups is similar. Thus, the addition of a third agent to an active doublet in the induction setting does not appear to increase overall efficacy, although long-term follow-up is needed.

Socinski and colleagues[20] reported on the GINEST (Gemcitabine in Neoadjuvant Early Stage Therapy) project, which comprises 2 randomized phase 2 trials evaluating 3 gemcitabine-containing regimens, as follows: cisplatin-gemcitabine, carboplatin-gemcitabine, and a nonplatinum doublet of gemcitabine-paclitaxel induction therapy. This report focused on the 83 treated patients with clinical stage I and II NSCLC. The complete resection rate is 73%; 70% underwent lobectomy,18% pneumonectomy, and 12% bilobectomy. Five percent were incompletely resected and 19% could not have surgery because either they did not respond to chemotherapy and had progressive disease (6%), had an adverse event (6%), were not suitable (5%), or refused (2%). Survival at 1 year is 84.9%. The data are still preliminary.

Building on the results of the BLOT trial,[21] which showed that preoperative carboplatin-paclitaxel was safe, feasible, and possibly improved survival, the Southwest Oncology Group (SWOG) opened S9900, a phase 3 trial[22] designed to compare neoadjuvant chemotherapy with surgery alone for patients with resectable IB, II, and IIIA (N2 negative) NSCLC. Although the trial closed early because adjuvant therapy became the standard of care and surgery alone was considered unethical, 354 patients had already enrolled in the study, with 180 patients in the neoadjuvant group; chemotherapy consisted of 3 cycles of carboplatin-paclitaxel. Resection status is available for 289 patients. Among 133 patients treated with neoadjuvant chemotherapy, complete resections were achieved in 95%, compared with 88% in the surgery-alone group. Neutropenia was the most prevalent toxicity, with nearly 50% of patients documented at > grade 3; febrile neutropenia > grade 3 occurred in 4% of induction patients. Compliance with induction chemotherapy was 77%; reasons for not completing treatment were as follows: adverse event (8%); refusal (4%)/progression (3%), death (2%), and other (6%). Neoadjuvant therapy in S9900 was feasible and produced similar 2-year survival rates (55%) as adjuvant chemotherapy. Overall survival is 47 months with preoperative therapy compared with 40 months for surgery alone; progression-free survival also favors chemotherapy followed by surgery compared with surgery alone: 31 months vs 20 months, respectively.

The 5-year results of the Scandinavian randomized trial of neoadjuvant carboplatin-paclitaxel vs surgery alone were also reported at this conference.[23] The study included patients with stages IB, IIA, IIB, or IIIA (N2 negative) disease. Patients were randomized to paclitaxel 225 mg/m2 and carboplatin AUC 6 on day 1 every 3 weeks followed by surgery or to surgery alone. Chest radiotherapy up to 60 Gy was administered if complete resection was not possible. A total of 280 patients were needed to demonstrate a statistically significant 5-year survival improvement of 15%, but unfortunately slow accrual prevented full enrollment. Among the 44 patients randomized to induction therapy, 46% had a PR, and microscopically complete resection was achieved in 79% of these patients. Median survival and 5-year survival for the investigational regimen were 34.4% and 36%, compared with 22.5% and 24% with surgery alone. Obviously, statistical differences were not significant based on inadequate sample size, as was the case in SWOG 9900, but the median survival increased by 1 year, and the 5-year survival rate increased by 50% in the experimental group, indicating a potential benefit with neoadjuvant therapy.

Conclusion

It must be pointed out that the results of neoadjuvant therapy trials reported here are all preliminary or incomplete. The magnitude of benefit from adjuvant therapy is estimated to be between 4% and 15%.[6-8] Compliance -- or lack of compliance -- with adjuvant chemotherapy is hypothesized as one of the reasons so many adjuvant trials prior to IALT failed to prove any survival benefit; age and nationality also influence compliance. Pneumonectomy patients are considerably less likely to complete adjuvant therapy than patients who undergo lesser resections.[24] If surgery is a factor in compliance with adjuvant therapy, then neoadjuvant therapy might be more tolerable and increase overall efficacy as suggested by survival trends in SWOG 9900 and the Scandinavian trial.

Although cisplatin-vinorelbine was the regimen used in the IALT, JBR.10, and ANITA adjuvant trials, the combination is not routinely administered in the United States. Future trials of adjuvant or neoadjuvant therapy will help to clarify the optimal regimen in terms of chemotherapy agents, dosage, and number of cycles, as well as the risk/benefit ratio of adjuvant or neoadjuvant chemotherapy for specific patient populations, such as the elderly (> 70 years old), those with borderline performance status, and IA-B disease. However, the next logical step toward refining treatment of early-stage NSCLC is to directly compare adjuvant and neoadjuvant chemotherapy for patients who are candidates for complete surgical resection.

Therefore, we are initiating a randomized phase 3 trial of adjuvant vs neoadjuvant cisplatin-docetaxel for stage IB, II, and IIIA (N2 negative) NSCLC patients with good performance status (ECOG PS 0-1), with survival as the primary end point (Figure 2). Meanwhile, the currently ongoing neoadjuvant paclitaxel-carboplatin hope (NATCH) trial is designed to compare survival among 600 patients randomized to receive 3 cycles of chemotherapy followed by surgery vs surgery alone, vs surgery followed by the same chemotherapy.[25] The trial includes patients with stages IA (T > 2 cm), IIA-IIB, and IIIA (T3N1) disease and will also analyze genetic markers that might help in predicting response, survival, and resistance. Currently, 513 patients are enrolled. The results of this trial will help to clarify the differences between neoadjuvant and adjuvant therapy for patients with early-stage, resectable disease.

[z]

Plans for surgery are a part of his study... so when they will be administering radiation and chemo, concurrently, they will be planning for surgery in the future.

They plan to go down the mediastanum (?) before the surgery, and after adiation. and remove all lymph nodes and biopsy them. If they are all negative, surgery is an option. If any of them come out positive, no surgery, but just follow up chemo.

It sounds violent and difficult to me, but that is it - supposedly the most aggressive therapy one can get, and maybe survive:)

Supposedly chances for long term survival are better.

They did some local study at UMMC - here is a link: http://ats.ctsnetjournals.org/cgi/conte ... code=annts

Z

[Darci]

I am certainly no expert on any of this, but this is what our surgeon told us.

When we first met with him, he said that they would do the mediatinscopy to ascertain whether the cancer had spread to my FIL's lymph nodes. If it had not - then they would do surgery to remove the lobe where the tumor is, then follow up with Chemo and radiation.

If it had spread, then they wanted to do a 6 week round of chemo and radiation, then the surgery.

Final result is that it is in one lymph node, but they are going ahead with surgery first. Not sure if any of this information will help you or not!!

Good luck...this is so hard, and it is so hard to know what is right. Maybe there is no "right" way to treat this??

[z]

Darci,

I believe it depends on where that lymph node is located. If it is just on the right side, than they would go ahead with surgery. If it is in the middle of the trachea, (carinal, like in my case), then they cannot operate right away.

My lymph nodes got biopsied with a bronchoscopy with needle aspiration (needle on the end of the bronchoscope) instead of mediastanoscopy (spelling?)

Z

[z]

Darci,

I believe it depends on where that lymph node is located. If it is just on the right side, than they would go ahead with surgery. If it is in the middle of the trachea, (carinal, like in my case), then they cannot operate right away.

My lymph nodes got biopsied with a bronchoscopy with needle aspiration (needle on the end of the bronchoscope) instead of mediastanoscopy (spelling?)

Z

[mhutch1366]

This was the exact protocol (almost) I was approached with 72 hours before surgery for my pancoast tumor. At that time, the rad onc had come up with an abstract from a conference that reported a p hase II clinical trial that ended 12 months out for immediate implementation.

I had the recommended course of treatment.

That was 5 years ago.

My understanding of the biochemistry of the tumor is that this approaches both solid visible tumor as well as micro mets, and provides against localized recurrence as well as metastases later, also providing for ( or against) accidental surgical spread of any malignant cells. The thinking is sound.

In my book, the more aggressive the treatment, the better off you will be. If it all works. After all, nothing ventured, nothing gained. If you don't pull out all the stops now, you cant get a pass go and a do over. Ya know?

There is plenty of previous experience with this protocol on pancoast NSCLC or superior suculus tumors. I had my surgery at NIH. Kasey had a similar treatment, but she found surgery and this doctor midway through a treatment. So this is not a new concept, it's been around since maybe... 98? Time enough to know about radiation and healing.

Best of luck to you.

XOXOX

MaryAnn

[z]

That is wonderful to hear, Mary Ann.

Is it rude, or silly, to ask - how was it, and how are you feeling now?

I fear the whole process... Already had 2 surgeries with my cervical cancer 7 years ago, and still feel the effects... even though, life has been relatively good until now.

Thanks,

Z

[john]

I believe there is a fair amount of evidence for induction (Neoadjuvant) chemotherapy then resection for Stage IIIA.

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Induction Chemotherapy and Radiation vs Radiation Alone in Stage III NSCLC

The use of systemic chemotherapy prior in "definitive" local-regional therapy (ie, therapy employing radiation, surgery, or both) is generally referred to as "induction chemotherapy" or "neoadjuvant chemotherapy." The term induction chemotherapy will be employed here.

The role of induction chemotherapy combined with thoracic radiation has been extensively investigated in patients with stage III NSCLC. While many phase II studies have been reported, numerous phase III studies also have been completed. Indeed, the role of induction chemotherapy is perhaps better supported by randomized studies in NSCLC than is the case for any other adult solid tumor. There are a number of theoretic advantages for the use of induction chemotherapy.16 These include stage reduction to facilitate improved local control by radiation, surgery, or both. The response rates to identical chemotherapy regimens appear to be higher when utilized for stage III disease than for stage IV disease. Micrometastases are addressed early in the course of treatment. Finally, some studies suggest that induction chemotherapy is better tolerated than chemotherapy administered later in the course of treatment.

Perhaps the most influential phase III trial in stage III NSCLC is CALGB 84–33.17 Eligibility for this trial was limited to patients with prognostically favorable pretreatment characteristics, including favorable performance status (Eastern Cooperative Oncology Group performance status, 0 or 1) and minimal weight loss (< 5% of body weight in the preceding 3 months). Patients were randomized to receive 60 Gy of radiation in 6 weeks or two cycles of induction chemotherapy with cisplatin and vinblastine followed by identical RT.

An update of this trial has been published that includes 7-year follow-up information.18 A total of 78 patients were randomized to chemoradiation, while 77 were randomized to RT alone. The objective response rate was 56% to combined treatment and 43% to RT alone (p = 0.092). The group randomized to induction chemotherapy achieved a significant improvement in median survival compared to the group randomized to RT alone (13.7 vs 9.6 months, respectively; p = 0.012) as well as improvement in the proportion of patients surviving 1, 2, 3, 5, and 7 years (54%, 26%, 24%, 17%, and 13% vs 40%, 13%, 10%, 6%, and 6%, respectively).

The Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group have conducted a confirmatory three-arm trial involving 452 eligible patients who were randomized to the same two treatment arms employed in study CALGB 84–33 as well as in a third arm that included hyperfractionation RT to a total dose of 69.6 Gy.19 The hyperfractionation RT arm had been demonstrated to produce a survival advantage for favorable patients in Radiation Therapy Oncology Group protocol 83–11.20 Preliminary results of the confirmatory trial indicate that the 1-year survival rate and median survival time were superior in the group randomized to receive induction chemotherapy compared to the other two groups (p = 0.03). The 1-year survival rate and median survival time for the three groups are as follows: induction chemotherapy and RT, 60% and 13.8 months, respectively; hyperfractionation RT, 51% and 12.3 months, respectively; and standard RT, 46% and 11.4 months, respectively.

Le Chevalier reported the results of a multicenter French study involving 353 patients who were randomized to 65-Gy radiation or to three cycles of induction chemotherapy employing cisplatin, vindesine, cyclophosphamide, and lomustine given prior to RT followed by three additional cycles of chemotherapy.21 22 The response rate to induction chemotherapy was 27%. One-, 2-, and 3-year survival rates for the combined chemotherapy/RT arm were 50%, 21%, and 11%, respectively, while for the RT-alone arm they were 41%, 14%, and 5%, respectively (p = 0.08). There was a very high rate of local-regional failure in both groups. Local control was 17% in the RT arm and 15% in the combined-modality arm in this trial. However, the distant failure rate was significantly reduced in the combined-modality arm compared to the RT arm (22% vs 46% failure at 1 year, respectively; p < 0.001). With a mean follow-up of 61 months, there was a statistically significant improvement in survival time associated with combined-modality treatment (p < 0.02).

The European Organization for Research and Treatment of Cancer conducted a three-arm study with 331 patients comparing 50-Gy thoracic RT in one arm to two other arms in which concurrent cisplatin and RT were utilized on one of two schedules.23 In one arm, cisplatin was administered daily (6 mg/m2/d) along with radiation, while in the other arm it was administered weekly (30 mg/m2/wk). There was a significant improvement (p = 0.009) in survival rates for daily cisplatin/radiation therapy compared with RT alone (2- and 3-year survival rates, 26% and 16% vs 13% and 2%, respectively). For weekly cisplatin therapy/RT, the survival rate was intermediate (2- and 3-year survival rates, 19% and 13%, respectively) but was not significantly different from either of the other arms. The survival benefit observed with daily cisplatin therapy/RT appeared to be secondary to that with improved local control (p = 0.003).

A meta-analysis has published that included data on 14 randomized trials comparing chemotherapy and RT to RT alone in regionally advanced stage III NSCLC.24 A total of 2,589 patients participated in these trials. Overall, the meta-analysis revealed that the use of combination chemotherapy and RT reduced the risk of death by 12% at 1 year, 13% at 2 years, and 17% at 3 years. This corresponds to a mean gain of life expectancy of about 2 months. Similarly, the magnitude of benefit was independent of whether sequential or concurrent chemotherapy and RT were utilized.

Despite encouraging data on the advantages of combined chemoradiation, many important questions remain unanswered. The optimal induction chemotherapy regimen has not been established. The optimal sequence of chemotherapy and RT remains unknown. The role of hyperfractionation RT has not been established.

Most importantly, the vast majority of patients continue to have recurrences of disease and eventually succumb to metastatic disease, despite the use of chemoradiation for regionally advanced NSCLC. Local-regional recurrence remains a major problem. In study CALGB 84–33, the group treated with chemoradiation had an 80% incidence of local-regional failure, while the group treated with RT alone had a 90% incidence of local-regional failure. Green25 has emphasized that patterns of failure despite induction chemotherapy and RT mandate better control of both macroscopic intrathoracic disease and distant micrometastatic disease in the setting of regionally advanced NSCLC.

Phase II Trials of Induction Chemotherapy, RT, and Surgery

Numerous phase II trials of induction chemotherapy and surgical resection in regionally advanced stage III NSCLC have been conducted. However, these trials vary considerably with respect to many factors. The variability relates to the use of surgical staging of the mediastinum, the delivery of RT with chemotherapy sequentially vs concurrently, the choice and dose of chemotherapeutic agents, RT dose schedules, and definitions of resectable disease. Such inconsistencies have led to considerable difficulties in the interpretation of these trials.

Table 2 lists 11 phase II trials of induction chemotherapy and surgery with or without RT in stage IIIA NSCLC.26 27 28 29 30 31 32 33 34 35 36 (Two trials also included patients with stage IIIB disease.26 36 ) Each of the trials listed utilized a cisplatin-based combination chemotherapy regimen. Seven of the trials used preoperative RT (in six trials, RT was administered concurrently with chemotherapy, and in one trial it was administered sequentially), two trials used only postoperative RT, and two trials did not employ RT at all.

View this table:

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Table 2. Phase II Trials on Induction Chemotherapy and Surgery in Stage IIIA Disease*

Overall, response rates to induction therapy were quite impressive, varying from 39 to 77%. Resectability rates exceeded 50% in each of these trials. The highest resectability rate (93%) was noted in a trial that utilized hyperfractionated RT concurrently with induction chemotherapy.31 Many trials report pathologic complete response rates in the range of 10 to 20% following induction chemotherapy. Median survival time and long-term survival rates varied significantly among the trials, but it is clear that a minority of patients had long-term survival and possible cure. Moreover, two multi-institutional trials showed that patients who were found to have negative N2 lymph nodes at the time of resection had a significantly better survival rate than those with persistent N2 positive disease at resection.30 36

None of these trials were designed to evaluate the therapeutic role of surgery in the context of regionally advanced disease, but the addition of surgery to the local-regional treatment regimen almost certainly accomplishes an improvement in local control. Local recurrence has generally been observed in < 50% of patients who undergo trimodality therapy. This contrasts with an 80 to 90% rate of persistent or recurrent local-regional disease among those patients who do not undergo resection.17 21 23 37 Thus, these phase II trials employing chemotherapy, RT, and surgery demonstrate a shift in recurrence patterns from both local and distant to predominantly distant. Furthermore, improved local control rates may result in significant gains in overall survival times as has been demonstrated by the reports of Schaake-Koning et al23 and Jeremic et al.38

Phase III Trials of Induction Chemotherapy and Surgery

Reports of small randomized trials comparing induction chemotherapy followed by surgical resection to resection without systemic treatment have been influential in modifying the perception of the role of chemotherapy in the management of regionally advanced NSCLC.

A study from Barcelona, Spain, randomized patients to an induction chemotherapy regimen of cisplatin, mitomycin C, and ifosfamide followed by resection and postoperative RT (50 Gy) or to resection and the same postoperative RT. There was a dramatic threefold survival advantage for those patients randomized to receive induction chemotherapy.39 In the group randomized to chemotherapy, the median survival time was 26 months, while in the group randomized to surgery plus RT, survival time was 8 months, which was lower than expected (p < 0.001).

In a similar trial conducted at the MD Anderson Cancer Center at the University of Texas, patients were randomized to induction chemotherapy consisting of three cycles of cyclophosphamide, etoposide, and cisplatin followed by resection or to surgical resection alone.40 Of note, RT was given to > 50% of patients in both arms of the study. The group that received chemotherapy achieved an estimated median survival time that was almost sixfold greater than that of patients randomized to surgery alone (64 vs 11 months, respectively; p < 0.008). Similarly, the 3-year survival rate was 56% for the induction chemotherapy group compared with 15% for the surgery-alone group.

While receiving much less attention than the other two trials, a third randomized trial from the National Cancer Institute preceded the other two.41 In this trial, the experimental group was treated with induction cisplatin and etoposide chemotherapy followed by resection and postoperative chemotherapy. The control group underwent immediate surgical resection and postoperative RT (54 to 60 Gy). Patients treated with induction chemotherapy had a superior survival time, but the difference was not statistically significant (28.7 vs 15.6 months, respectively).

A fourth randomized trial that was conducted by the CALGB is not yet fully mature.42 The experimental arm of this study consisted of induction chemotherapy with cisplatin and etoposide for two cycles followed by resection, two additional cycles of chemotherapy, and subsequent RT (54 or 60 Gy). The control arm consisted of preoperative RT (40 Gy), resection, and postoperative RT (to a total dose of 54 or 60 Gy). Preliminary results show that the median overall survival time was 19 months for the group undergoing induction chemotherapy compared with 23 months for the group receiving preoperative RT. While the trend toward reduced survival time in the group receiving induction chemotherapy was not statistically significant, the results of study CALGB 9134 conflict with the results of the other three randomized trials, which suggest a dramatic benefit with the use of induction chemotherapy.

Although three of the four randomized trials showed a survival benefit with the use of induction chemotherapy (including two trials in which the differences were statistically significant), these studies have significant limitations that raise important questions as to whether induction chemotherapy has been proven to be beneficial. One major problem relates to the fact that each of the trials enrolled small numbers of patients (Barcelona trial, 60 patients; MD Anderson Cancer Center trial, 60 patients; National Cancer Institute, 27 patients; and CALGB, 57 patients). The Barcelona and MD Anderson Cancer Center trials were discontinued before the projected accrual goal was reached because of early stopping rules. The highly publicized beneficial effects observed in the Barcelona and MD Anderson Cancer Center trials were most likely responsible for difficulty in accruing patients to study CALGB 9134, leading to its premature closure. Furthermore, the absolute magnitude of the survival differences seen in the MD Anderson Cancer Center and Barcelona trials were far greater than reasonably could be expected from the modestly effective chemotherapy regimens employed. These extreme results should raise caution. A plausible explanation for the magnitude of the differences seen in these studies is that, despite the process of randomization, there may have been an imbalance of prognostic factors between the arms. In the Barcelona study, it was demonstrated that the group of patients randomized to surgery alone included a higher fraction of tumors with the more virulent characteristics of K-ras mutations (42% vs 15%, respectively) and DNA aneuploidy (70% vs 29%, respectively).39 43 Hence, it is possible that an excess of biologically virulent tumors in the group randomized to surgery alone in the Barcelona study is responsible for the observed outcome differences rather than a beneficial effect of the induction chemotherapy itself. While there is no direct evidence for a similar imbalance in the MD Anderson Cancer Center trial, prognostically important molecular markers were not considered in this study. Possibly, an imbalance of some unmeasured prognostic variable might have contributed to the magnitude of the differences seen in this trial.

Cumulatively, these four phase III studies evaluating the role of induction chemotherapy followed by surgery have included a total of only 204 patients. The results are surprising and conflicting. Accordingly, the benefit of induction chemotherapy, although suggested, has not been definitively demonstrated. The 11 phase II studies listed in Table 2 include 781 patients. While the results of these trials vary, there is greater consistency in the results of the phase II trials than of the randomized trials.

Conclusion

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Abstract

Introduction

Ongoing Trials of Adjuvant...

Role of Induction Chemotherapy...

Conclusion

References

Despite the limitations of the randomized induction chemotherapy and surgery trials in stage IIIA NSCLC, the results of these trials lend some support to the conclusion that for favorable patients with stage IIIA NSCLC, induction chemotherapy followed by resection (with or without RT) may enhance disease outcome compared with that achieved with resection (with or without RT). While the magnitude of the survival advantages added by chemotherapy are very likely to have been exaggerated, particularly in the MD Anderson Cancer Center trial, numerous phase II trimodality studies support a similar conclusion, though with a modest degree of effectiveness. In addition, these results for induction chemotherapy with surgery are consistent with numerous phase III studies that have demonstrated that induction chemotherapy with definitive RT improves outcome when compared with thoracic RT alone.

Whether induction chemotherapy is now the standard therapy is debatable, but there is a clear suggestion of benefit, and additional clinical trials evaluating this approach will be difficult to accomplish. The role of resection in stage IIIA disease remains unproved, but local control appears improved in multimodality programs that include resection, and patients found to have negative N2 nodes at resection do quite well. A phase III trial designed to evaluate the efficacy of surgical resection in the context of induction chemoradiation in stage IIIA NSCLC is currently ongoing by several cooperative groups under the leadership of the Southwest Oncology Group. Conventional RT approaches are probably not optimal.

The recent results of both phase III and phase II trials provide a basis for optimism that real therapeutic progress is finally being achieved in regionally advanced NSCLC. Further study of therapeutic strategies that incorporate aggressive systemic treatment and maximal local-regional therapy in stage III NSCLC is clearly warranted.