A Phase II Clinical Trial of Sequential Neoadjuvant Chemotherapy with Ifosfamide, Doxorubicin, and Gemcitabine, followed by Cisplatin, Gemcitabine, and Ifosfamide in Locally Advanced Urothelial Cancer: Final Results

Abstract

Introduction

Neoadjuvant chemotherapy improves survival in high-risk urothelial cancer. However, the lack of curative alternatives to cisplatin-based chemotherapy is limiting for patients with neuropathy or hearing loss. Sequential chemotherapy is also not well studied in the neoadjuvant setting. We explored sequential neoadjuvant ifosfamide-based chemotherapy in a patient cohort at “high-risk” of non-curative cystectomy.

Methods

Patients with muscle-invasive cancer and lymphovascular invasion, hydronephrosis, cT3b-4a disease (3D mass on EUA, or invasion into local organs), micropapillary tumors, or upper tract disease, received 3 cycles IAG followed by 4 cycles CGI. The primary endpoint was down-staging to ≤ pT1N0M0.

Results

With median follow-up of 85.3 months, the 5-year overall survival (OS) and disease-specific survival for all 65 patients was 63% and 68%, respectively (95% CI 5-yr OS: 0.52–0.76 and DSS: 0.58–0.81). Pathologic staging of ≤ pT1N0 occurred in 50% at cystectomy, and 60% at nephroureterectomy and correlated with 5-year OS: ≤ pT1N0, 87%; pT2–3aN0, 67%; and ≥ pT3b or N+, 27% (p ≤ 0.001 comparing ≤ pT1 vs. ≥ pT2). Variant histology was associated with inferior 5-year DSS: 50% vs. 83% in pure TCC (p=0.02). The most frequent grade 3 toxicities were infection (38%), febrile neutropenia (22%), and mucositis (18%). There were three grade 4 toxicities (myocardial infarction, thrombocytopenia, and vomiting), and one grade 5 in a patient who refused antibiotics for pneumonia.

Conclusions

Sequential therapy was active, maintaining the historical expectation of cure. These results strongly reinforce previous experience suggesting that pathologic staging of ≤ pT1N0 is a useful surrogate for eventual cure.

INTRODUCTION

Neoadjuvant chemotherapy is the standard in treating surgically resectable invasive urothelial cancer^{1, 2} However, neoadjuvant chemotherapy still remains largely underutilized out of concern that the risks, especially the toxic effects of chemotherapy, may outweigh the benefits of treatment. At a previous plenary session at ASCO, the merits of neoadjuvant chemotherapy were debated.^{3, 4} Much work is needed to improve the survival, and reduce the toxicity for our patients with bladder cancer.

Sequential chemotherapy, as one potential method of improving survival, has not yet been explored in the neoadjuvant setting. Clinical trials in the metastatic setting have not observed any definitive benefit and have been limited by their fixed schedules.⁵ Using a sequence employing a “for cause” determination, where chemotherapy that is working is continued longer and switched early when there is a lack of response, may provide additional benefit.⁶ Using a “for-cause” sequential approach in the metastatic setting, we have seen a potential improvement in surgical consolidation of lymph node metastases.⁷

On the other side of the neoadjuvant debate is the toxicity of therapy. With the understanding that many patients are not candidates for cisplatin-based chemotherapy as a result of pre-existing peripheral neuropathy and/or hearing loss, we developed chemotherapy regimens using the alkylating agent ifosfamide as its backbone. Pre-clinical data suggested enhanced DNA damage with combinations incorporating a nucleoside (gemcitabine) with an alkylating agent (ifosfamide or cisplatin).⁸ Two combinations arose from this process, one maximizing the alkylating agent and minimizing the nucleoside (ifosfamide, doxorubicin, gemcitabine – IAG),⁹ and the other maximizing the nucleoside agent gemcitabine with much lower doses of alkylating agents(cisplatin, gemcitabine, ifosfamide – CGI).¹⁰ Using this combination sequentially, we hoped to overcome potential chemotherapy-resistant cells, with the goal of improving response and enhancing the long-term survival for these patients. Additionally, since this sequence used a much lower cumulative dose of cisplatin, we hoped to avoid peripheral neuropathy, and provide an alternative active regimen for patients with pre-existing peripheral neuropathy or baseline hearing loss.

Previous work from our group also suggested that clinical and pathologic features predict for a high-likelihood of extra-organ extension with pathologic upstaging in up to 86% of patients.¹¹ This suggests a group at particularly high risk from their cancer, who would be candidates for aggressive sequential chemotherapy. We now report final results of this phase II clinical trial of sequential neoadjuvant chemotherapy in patients with high-risk, surgically resectable urothelial cancer.

METHODS

From August 2001 to April 2006, 65 patients enrolled onto this M. D. Anderson Institutional Review Board approved clinical trial. All patients had surgically-resectable urothelial carcinoma, and were selected for being at high-risk of non-curative resection by virtue of the following features: a 3-dimensional mass on examination under anesthesia performed after thorough TUR; tumor invasion into the prostatic stroma, vagina, or uterus (clinical T4a); lymphovascular invasion; hydronephrosis; micropapillary histology; or high-grade upper tract cancer of the ureter or renal pelvis. Patients not conventionally considered resectable with curative intent, (tumors fixed to the pelvic sidewall (clinical T4b), or any evidence of nodal involvement or distant metastases) were not eligible for this clinical trial. No prior systemic chemotherapy was allowed; however, patients may have received any prior intravesical therapy.

Patients had adequate physiologic reserve, with a Zubrod performance status ≤ 2, or 3 if of recent onset and due entirely to the cancer and not to a co-morbid medical condition. Adequate bone marrow reserve was defined as an absolute neutrophil count > 1800 at baseline and a platelet count > 150,000. Adequate liver function required a transaminase ≤ three times the upper limit of normal, with a conjugated bilirubin ≤ 1.5 mg/dl or total bilirubin ≤ 2.5 mg/dl. Patients required a creatinine clearance either measured or by Cockcroft-Gault of ≥ 45 ml/min. The presence of an abnormal EKG or a history of heart disease required an ejection faction ≥ of 50% to be eligible for this trial.

CHEMOTHERAPY

Sequential chemotherapy consisted of 3 cycles of IAG, followed by 4 cycles of CGI. If inadequate response was observed during the repeat 6 week cystoscopy, patients were switched after 2 cycles IAG to 6 cycles of CGI.

Initially, the doses for IAG were: ifosfamide 2000 mg/m² daily with MESNa day 1–4, doxorubicin 50 mg/m² day 3, and gemcitabine at 200 mg/m² on day 2 and day 4. However, 4 of the first 10 patients experienced toxicity, especially myelosuppression, necessitating a dose-reduction. The starting doses were modified in subsequent patients: ifosfamide 1500 mg/m² infused over three hours daily, day 1–4; with MESNa 225 mg/m², over 15 minutes, at hours zero, three, seven, and eleven daily, day 1–4; doxorubicin 45 mg/m² over 15 minutes via peripheral IV or up to 12–18 hours via central line on day three only; and gemcitabine 150 mg/m² over 30 minutes on day 2 and day four only.

While receiving IAG, patients were aggressively hydrated, frequently utilizing a sodium acetate infusion. Methylene blue with or without albumin was administered in the event of neurological toxicity; ifosfamide was reduced in subsequent cycles if neurological symptoms recurred despite treatment with methylene blue. Serum creatinine was monitored on a daily basis, with treatment held if renal insufficiency developed. Nearly all patients with hydronephrosis had a nephrostomy tube placed prior to chemotherapy, even in the setting of normal serum creatinine, to help maintain renal function. This inpatient regimen was repeated on three-week intervals with growth factor support.

The doses for CGI were: gemcitabine 900 mg/m² over 90 minutes day 1, ifosfamide 1,000 mg/m² over 60 minutes on day 1, followed by cisplatin 50 mg/m² in 500 ml normal saline with 12.5 gm of Mannitol over 3 hours on day 1. MESNa was not required with this low dose of ifosfamide. The cisplatin was typically followed by a mannitol infusion consisting of D5-1/4 normal saline with mannitol 40 gm/liter for at least 2–3 liters. This inpatient or outpatient regimen was repeated at 2-week intervals, with growth factor support as necessary.

CLINICAL EVALUATION

Within six weeks of study entry, patients received either a CT scan or an MRI scan of the abdomen and pelvis and a chest x-ray or CT of the chest, and an EKG within six months. A baseline bone-scan was only required in the presence of bone pain, or an elevated calcium or alkaline phosphatase. Prior to registration, all patients must have been seen by a member of the Department of Urology and have had a cystoscopy with a thorough transurethral resection (TUR) of bladder tumor, and exam under anesthesia to evaluate for the presence of a three-dimensional mass, and to evaluate for bladder mobility. After 6 weeks of treatment, patients had a repeat cystoscopy and TUR to evaluate for response. All patients were recommended for cystectomy regardless of the degree of response observed in the bladder.

RESPONSE CRITERIA

A major response was defined as ≤ pT1N0 at the time of cystectomy. Responses of lesser magnitude were scored as treatment failure. Progression was counted as any objective sign of recurrent or progressive disease. If symptoms pre-dated histologic or radiographic confirmation of recurrence, the date of progression was taken as the date of onset of symptoms.

STATISTICAL CONSIDERATIONS

The primary endpoint of this trial was down-staging to ≤ pathologic T1N0 after chemotherapy, an endpoint well–described as a surrogate for eventual cure. Simon’s two-stage minimax design was used.¹² Assuming an a priori response rate of 35% (p₀ = 0.35), with an expected response of 50% (p₁ = 0.50) with neoadjuvant therapy, this study required 49 patients to provide 80% power with α = 0.10. Upon passing into the second stage, it required at least 22 responses out of 49 patients to be considered successful for further study. An additional 16 patients were accrued to account for patients refusing surgery, progressing to unresectable tumor, or who were treated for upper tract urothelial cancer. All patients receiving any chemotherapy were included in the final analysis. The probability of early termination under p₀ is 0.46, and the expected sample size is 40.8.

Kaplan-Meier curves were used to estimate the overall survival, and disease-specific survival distributions. The 5-year survival probability and its corresponding 95% confidence interval were provided for each study cohort. Nonparametric log-rank test was used to compare the survival curves by pathologic stage or by histology. A multivariate Cox proportional hazards model was used to explore the effects of tumor characteristics on survival. The proportional hazards assumption was verified using the test statistic based on weighted residuals. All statistical tests are two-sided at significance level of 0.05

RESULTS

PATIENT CHARACTERISTICS

Baseline characteristics for all 65 patients are listed in Table 1. Please note that all patients had at least one of the high-risk features noted in the “Methods” section. All patients had a histologic diagnosis of urothelial carcinoma; 43% of patients had another variant histology, such as micropapillary, squamous, adenocarcinoma, or sarcomatoid changes associated with their urothelial tumor. In all instances, except in the setting of micropapillary tumors, the variant histology must have been present in less than 50% of the tumor specimen to be considered eligible for this trial.

Table 1.

Patient Characteristics

	No.	%
Age
Median	62.5
Range	34–82
Gender
Male	50	77
Female	15	23
PS
0	41	63
1	24	37
Site of Primary
Bladder/Urethra	60	92
cT2	37	62
cT3b	18	30
cT4a	5	8
Renal Pelvis/Ureter	5	8
Histology @diagnosis)
TCC only	37	57
TCC + Variant	28	43
Micropapillary	13	20
LVI	34	57
Hydronephrosis	14	22

RESPONSE AND SURVIVAL

Overall, pathologic down-staging to less than or equal to pathologic T1 occurred in 30 of 60 (50%) of patients with bladder primaries (Table 2), and 3 of 5 patients with renal pelvis primaries, with a pT0 rate of 43%, and 0%, respectively. Down-staging correlated with 5-year overall survival (log-rank p ≤ 0.001): patients down-staged to ≤ pT1N0, pT2-3aN0, and ≥ pT3b or N+ tumors had an 87%, 67%, and 27% 5-year overall survival, respectively (Figure 1). For patients completing 3 cycles of IAG prior to CGI, the pT0N0 and ≤pT1N0, rates were 60 and 65%, respectively. For those treated with 2 or fewer cycles of IAG and switched early to CGI due to lack of response or toxicity, the pT0N0 and ≤pT1N0 rates were 17 and 26%, respectively. This likely reflects the poor biology seen in non-responding patients, who typically have aggressive tumors and poor outcomes. There were only 2 patients who failed to respond to IAG and were pT0 following CGI. As has been observed in other studies, the absence of residual disease on repeat, post-chemotherapy cystoscopy is not a guarantee of pT0N0. In our experience, even when there was no visible tumor remaining on repeat cystoscopy, 42% of patients had residual tumor present at cystectomy.

Table 2.

Clinical versus pathologic stage at cystectomy.

	pT0N0	pT1N0	pT2N0	pT3/4aN0	pT4b, N+, or M+
cT2N0	20	3	3	0	9
cT3bN0	6	0	3	5	3
cT4aN0	0	1	1	0	1

Refused surgery: cT4aN0 (2 pts), cT2N0 (2 pts); Toxic death (cT3bN0)

Figure 1.

Overall survival distribution by pathologic stage. For all patients enrolled, pathologic down-staging to ≤ pT1N0 occurred in 51% of patients. Down-staging correlated with improvement in overall survival (p ≤ 0.001 comparing ≤pT3aN0 with ≥pT3b, or N+.) Patients down-staged to ≤pT1N0, pT2-3aN0, and ≥pT3b or N+, had a 5-year OS of 86%, 67%, and 27%, respectively.

For all patients enrolled, the combined 5-year overall survival (OS) and disease-specific survival (DSS) was 63% and 68%, respectively (95% CI: five-year overall survival = 52–76% for OS and 58–81% DSS with a median follow-up of 85.3 months) (Figure 2). In patients undergoing node dissection for bladder primaries, the median number of lymph nodes removed was 12 (range 3–39). Three patients did not undergo node dissection as a result of prior abdominal surgery, or prior node dissection (ie:prior prostate cancer). All patients who progressed did so within 18 months of their surgery, except for one late progression in the lung at 53 months. There was some concern that the lung finding reflected a second primary cancer; however, since the scans were not available for review at our institution, we counted this patient as having progressive urothelial cancer.

Figure 2.

Overall survival distribution. For all patients enrolled, the 5-year overall survival was 63% (95% confidence intervals shown).

The presence of variant histology was associated with an inferior 5-year DSS of 50% (95% CI = 35–72%) as compared to 83% (95% CI = 71–96%) for pure transitional cell carcinoma (log-rank p= 0.02, Figure 3). Though there is a similar trend for the histology on OS, the difference in OS was not statistically significant (log-rank p = 0.1451). The presence of micropapillary histology was associated with a 5-year OS and DSS of 54% (95% CI 33–89%).

Figure 3.

Disease-specific survival by histology. For all patients enrolled, patients with a pure transitional cell histology had a longer disease-specific survival, as compared with patients whose tumors expressed variant histology (DSS 83%, and 50%, respectively, log-rank p = 0.02).

In the multivariate Cox model, whether a patient with primary bladder cancer (n=60) had down-staging to ≤ pT1N0M0 after chemotherapy is a statistically significant predictor (relative risk is 0.13 with 95% CI=.04 –.40 for down-staging versus not, p<0.001) and pure TCC histology is also a significant factor to disease-specific survival (relative risk is 0.35 with 95% CI = .14 – .89 for TCC vs. mixed, p=0.03), while other tumor characteristics (clinical stage at diagnosis, hydronephrosis, micropapillary tumor, lymphovascular invasion (LVI), and performance status) are not statistically significant in the multivariate models. The proportional hazards model assumption is satisfied for both risk factors. In the multivariate Cox model, tumor histology (TCC vs. mixed) is not statistically significantly associated with OS endpoint, whereas patient’s down-staging is always significantly associated with OS endpoint. Similar findings were observed when upper tract patients were included in the analysis (n=65) where final pathology of ≤ pT1N0M0 remained statistically significant (p<0.001), whereas pure TCC histology was marginally significant (p = 0.07).

TOXICITY

These 65 patients received 166 cycles of IAG, and 196 cycles of CGI. The only treatment-related death was pneumonia during neutropenia, which occurred in Cycle 1. This patient refused additional therapy, including antibiotics, and quickly succumbed to the pneumonia. Three patients experienced Grade 4 toxicities: myocardial infarction, platelet transfusion, and vomiting. The most frequent Grade 3 toxicities (Table 3) were infection (38%), febrile neutropenia (22%), mucositis 18% and platelet transfusion (12%). Notably, no patients developed peripheral neuropathy as a result of this chemotherapy. Three patients discontinued IAG after their first cycle; one who experienced a fatal toxicity as described earlier, a second who developed renal insufficiency, and the third whose tumor progressed rapidly. Eleven patients required dose reduction of IAG, while 10 required dose reduction for CGI. Forty patients completed all 3 cycles of IAG. Of the 25 transitioned early to CGI, 13 were due to lack of response, 3 for patient choice, and 9 for toxicity or physician concern about ability to complete all 3 cycles. Seven of these 9 patients were treated at an ifosfamide dose of 2000 mg/m². After the first 10 patients were treated, the dose of ifosfamide was decreased to 1500 mg/m², which was much more tolerable.

Table 3.

Toxicity – Chemotherapy Related

Chemotherapy-Related	No. Pts.	%
Grade 5
Infection*	1	2
Grade 4
Myocardial Infarction	1	2
Platelet transfusion	1	2
Vomiting	1	2
Grade 3
Infection	25	38
Febrile Neutropenia	14	22
Mucositis	12	18
Platelet Transfusion	8	12
Catheter-related thrombus	5	8
Dehydration	5	8
Fatigue	5	8
Nausea/Vomiting	4	6
PRBC Transfusion	3	5
Catheter-related infection	2	3
Chest pain	2	3
Diarrhea	2	3
Pain	2	3

Additional grade 3 toxicity (1 patient each): arthralgia, dyspnea, rash, hallucination, thrombosis/embolus, vasovagal reaction

^*Neutropenic fever/pneumonia in C#1, refused additional treatment, including antibiotics.

SURGICAL COMPLICATIONS

The median hospital stay for patients undergoing a cystectomy was eight days (range: 4 to 38 days) (Table 4). There were no perioperative deaths. Six patients received 5 or more units of packed red blood cells post-operatively; however, many of these patients were anemic as a result of their neoadjuvant chemotherapy. Two patients had repeat surgery within the perioperative period: 1 for bowel obstruction who required lysis of adhesions with an area of bowel torsion, and 1 for a patient who required embolectomy for an arterial thrombus in their aorto-femoral grafts. A full listing of perioperative complications within a 30 day period are listed in Table 4. Ten patients did not undergo surgery: six patients declined surgery despite our firm recommendation, while four progressed - two in the bone and two elsewhere in the bladder and lung. Unfortunately, all patients who declined surgery had a relapse of their cancer.

Table 4.

Surgical Parameters and Perioperative Morbidity

Post-surgical (N=55)	No.
Median hospital stay	8 d
Range	4–38
Diversion Type
Ileal Conduit	24 (44%)
Orthotopic Neobladder	22 (40%)
Indiana Pouch	4 (7%)
Nephroureterectomy	5 (9%)
Positive Margins
Serosal	1 (2%)
Perioperative Deaths	0
Cardiovascular
Ischemia	1 (2%)
Arrhythmia	1 (2%)
Thrombotic
Pulmonary Embolus	1 (2%)
Arterial thrombusa	1 (2%)
Gastrointestinal
Ileusb	4 (7%)
Small bowel Obstructionc	1 (2%)
Pancreatitis	1 (2%)
Infection
Pneumonia	4 (7%)
Urinary Tract	1 (2%)
Wound	2 (4%)
No obvious source	3 (5%)
Transfusion >= 5U PRBC	6 (11%)
Acute renal insufficiency	2 (4%)
Surgical
Urine Leak	2 (4%)
Skin dehiscence	6 (11%)
Fascial dehiscence	0
Rectal Laceration	2 (4%)
Obturator Nerve Damage	1 (2%)
No surgery	10
Patient Decision	6
Bone metastases	2
Progression (bladder and lung)	2

^a: Patient with aorto-bifemoral grafts, required embolectomy

^b: Requiring delay in discharge more than 10 days from surgery

^c: Adhesions and bowel torsion requiring surgery

DISCUSSION

Overall, 69% of the patients we studied were cured of their high-risk bladder cancer. Importantly, our results confirm that neoadjuvant chemotherapy resulting in no residual muscle-invasive cancer in the cystectomy specimen is highly associated with overall survival and disease-specific survival. The present results are similar as compared to those in our previous randomized trial of neoadjuvant versus adjuvant M-VAC in a similar high-risk cohort¹³ and to those of the SWOG Intergroup Study,¹ with a retrospective study of the latter showing a survival benefit for ≤pT1N0 disease.¹⁴ The consistency of these findings firmly establishes that pathologic response is a useful early surrogate for eventual cure.

This trial used sequential chemotherapy in the hopes of enhancing pathological response and overall cure. As compared to other trials in the metastatic setting which used fixed sequences,⁵ this trial used a “for cause” approach for switching to the second sequence.⁶ Patients had a repeat cystoscopy after the first 2 cycles, and if responding, received additional IAG; non-responders were switched earlier to CGI. However, the similar pathologic down-staging rates and survival as with previous neoadjuvant trials suggest no additional benefit from this sequential approach. It is possible that patients who did not respond to chemotherapy had such poor biology that they would not have responded to any chemotherapy that was given. Only 2 patients who were switched early for failing to respond to IAG were pT0 following CGI. It is also possible that the combination of CGI, which utilizes lower doses of cisplatin and ifosfamide, may not be sufficient to overcome resistance to the initial chemotherapy. Therefore, sequencing with a high dose of ifosfamide/low dose gemcitabine with a regimen with low dose ifosfamide/high dose gemcitabine, may not have been as complementary as we had originally anticipated.

While IAG was associated with toxicity, there was, notably, no peripheral neuropathy. Despite the toxicity, 100% percent of patients received at least one cycle of IAG, 93% at least 2 cycles, and 61% 3 cycles of IAG. While the sequential therapy we investigated does not seem suitable for use outside the setting of dedicated, multi-specialty care, IAG may be an attractive option for fit patients with pre-existing peripheral neuropathy or hearing loss, who are at risk for worsening of these conditions with the use of cisplatin-based chemotherapy. However, our experience suggests that to tolerate high-dose ifosfamide in this elderly patient group, requires adequate renal function, with a creatinine clearance around 50 ml/min or greater, and the use of nephrostomy tubes in the setting of obstructed kidneys. We have also found this regimen is difficult for most people in their 80’s to tolerate, and would not recommend its use in this age group.

We used clinical criteria to select for patients with a higher risk of having extra-organ extension or nodal involvement at cystectomy. On a previous clinical trial randomizing patients to either initial cystectomy or neoadjuvant chemotherapy, the presence of these high-risk features was associated with clinical up-staging in 86% of patients treated with initial surgery.¹³ Patients with muscle invasive tumors only (without high risk features) were not eligible for this trial, and have traditionally been treated at our institution with initial cystectomy, to be followed by adjuvant chemotherapy in the presence of extra-organ extension or nodal involvement. A retrospective review of our experience with this strategy suggests that we can achieve similar long-term outcomes, sparing many patients from the toxicity of systemic chemotherapy (manuscript in preparation). This is especially important when avoiding toxicity of chemotherapy in a population of patients who are frequently elderly with co-morbid medical conditions.

However, the application of our high-risk criteria may be difficult to apply in the community setting. For example, the determination of lymphovascular invasion on a TUR specimen, to be distinguished from retraction artifact, requires an experienced pathologist. Examination under anesthesia to determine tumor beyond the wall of the bladder requires an urologist skilled in this exam, and a thorough trans-urethral resection. The treatment we describe is a truly multi-disciplinary collaboration between urologists, pathologists, and genitourinary medical oncologists that may be difficult to achieve outside the context of a tertiary center.

While the present results may be slightly better than historical expectation, it is clear that the cohort we studied continues to have a disappointing prognosis despite very aggressive application of chemotherapy and surgery. Current treatment fails for about one-third of patients with high risk bladder cancer, and those with persistent extravesical or nodal disease despite primary chemotherapy have an especially poor prognosis. The ability to identify those patients unlikely to benefit from primary chemotherapy would allow us to explore alternative strategies, and is an important research objective. One such alternative, based on our previous finding that VEG-F expression is a powerful predictor of outcome in this cohort,¹⁵ is the combination of bevacizumab with neoadjuvant chemotherapy. This is the current strategy under investigation in our center.

Conclusions

Similar response and survival were seen with this combination as compared to a similar cohort treated with neoadjuvant MVAC chemotherapy. The toxicity profile of this combination provides a useful alternative in the setting of peripheral neuropathy or hearing loss. However, the use of high-dose ifosfamide can be difficult in this patient population, requiring dedicated toxicity management, and may be more suitable to a tertiary care facility. The presence of advanced disease despite preoperative chemotherapy continues to have a poor prognosis; the ability to select these patients prior to chemotherapy would provide a cohort for initial surgery or chemotherapy combinations overcoming their resistance pathways. These results reinforce previous experience suggesting that pathologic down-staging to <=pT1N0 is a useful surrogate for eventual cure.