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Neoadjuvant Chemotherapy Is Not (Yet) Standard Treatment for Muscle-Invasive Bladder Cancer

From the Vincenzo Pansadoro Foundation, Rome, Italy, and the Medical Research Council Clinical Trials Unit, London, United Kingdom.

Address reprint requests to Cora N. Sternberg, MD, FACP, Vincenzo Pansadoro Foundation, Clinic Pio XI, Via Aurelia 559, Rome, Italy 00165; email: cstern{at}mclink.it

	INTRODUCTION

TOP INTRODUCTION HOW SHOULD WE INTERPRET... REFERENCES

 
AT THE PLENARY SESSION of the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology (ASCO), I (C.S.) was asked to discuss the Intergroup study 0080, coordinated by the South Western Oncology Group (SWOG) with participation of the Eastern Cooperative Oncology Group and Cancer and Leukaemia Group B (CALGB). In this trial, patients with locally advanced bladder cancer were randomized to receive either three cycles of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy before cystectomy versus cystectomy alone.

The role specified for this discussion was to be critical and provocative with an emphasis on the uncertainties in the trial and its results. The presentation focused on whether we should change our clinical practice on the basis of this one trial. To help address this question, the presentation was organized into five sections:

1. How should we interpret this trial?
   
2. Is neoadjuvant or adjuvant chemotherapy likely to be more successful?
   
3. What is the best chemotherapy to test and use?
   
4. Can chemotherapy clear and spare the bladder?
   
5. What is current best standard treatment?
   

	HOW SHOULD WE INTERPRET THIS TRIAL?

TOP INTRODUCTION HOW SHOULD WE INTERPRET... REFERENCES

 
The aim of the SWOG trial was to detect an increase in survival with the use of neoadjuvant MVAC chemotherapy. The study was planned for one-sided testing, which means that it was not to test for a difference but only for improvement. The investigators who planned the study reasoned that medical practice would change only if there were an improvement with chemotherapy. They were not interested in the possibility of adverse effects on survival of the chemotherapy. This is not logical, considering that MVAC is not benign therapy and is associated with significant morbidity and mortality.¹ In the large International Intergroup trial that used neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy, a 1% mortality was due to CMV chemotherapy.² The design of a clinical trial is important, and informative and reliable clinical trials are needed. As a rule of thumb, 30% more events must be observed for two-sided testing than for one-sided testing. Most randomized trials undertake two-sided testing. In one sense, the argument between one-sided and two-sided testing is academic; the important point is that for comparing results across trials, it is important that the results be presented in the same way—either all one-sided or all two-sided.

It is useful to consider the size of the SWOG trial. A trial with adequate power for the detection of a 10% survival advantage of investigational chemotherapy over standard therapy (60% 3-year survival for patients who received chemotherapy compared with 50% in those who were treated with local therapy alone) will require approximately 1,000 patients to be randomized over a 3- to 4-year period with an additional 1 to 2 years of follow-up.³ This is because approximately 400 deaths are required to be observed for the study to have a 90% chance of detecting this difference (it is, of course, the number of deaths that determines the information content and power of a trial).⁴ In a smaller study of approximately 400 patients recruited over a period of 3 to 4 years, typically 170 deaths would be observed and based on a two-sided log-rank test (alpha = 0.05; 85% power), and we would be able to detect reliably differences of the order of 15% (from 50% to 65%). The SWOG trial recruited 307 patients; because of the long accrual period, a total of 186 deaths were observed. Thus, the SWOG trial realistically could detect large improvements in survival only of the order of 15% in absolute terms.

Although SWOG should be complemented for completing this trial, this study was started 14 years ago and the accrual to this trial was over an 11-year period, which means that approximately two patients per month in the entire United States were enrolled onto the trial. How do we interpret such a trial? Standards of diagnosis, patient care, and surgery have changed over this long period of patient entry. Patient selection may play an important role in who was enrolled onto this trial. Of note, 40% of the patients entered onto both arms had a "good" prognosis, with T2 disease. That means that a high proportion of these patients easily may have been cured by cystectomy alone. In addition, among the "eligible" patients in both arms of the trial, only 80% of the planned cystectomies were performed.

As is widely accepted now, results of a single trial rarely are sufficient, and one must consider all of the evidence from all relevant randomized trials.⁵ Table 1 displays the results of all of the randomized neoadjuvant chemotherapy trials of which we are aware.^2,6-14 The first thing to note is that a number of trials have a very similar design and the differences between trials stem largely from the use of different types of chemotherapy. However, it is clear that the SWOG trial represents only 10% of all patients randomized into trials of neoadjuvant chemotherapy, and we need to consider it in this context.

The International Intergroup trial of CMV chemotherapy before cystectomy or radiotherapy is the largest trial of neoadjuvant chemotherapy. In almost 1,000 patients randomized, it showed a small difference in survival, in favor of the chemotherapy group, that was not statistically significant at conventional levels of significance.² The Nordic cystectomy I trial reported a small difference only in a subgroup analysis of patients with T3 to T4 disease⁶ but could not confirm this in the Nordic II trial.¹³ An almost identical trial to that performed by the SWOG was done by the Italian Gruppo Uro-Oncologico del Nord-Est (GUONE), and patients were randomized to receive either four cycles of MVAC given before cystectomy or cystectomy alone. No clear evidence of a difference was observed.⁷ No evidence of a difference in survival was seen in another Italian trial of methotrexate, vinblastine, epirubicin, and cisplatin versus cystectomy, when epirubicin was substituted for doxorubicin.¹⁵

As the largest trial, representing approximately one third of the patients, it is worth examining the International Intergroup (BA06/30894) trial in more detail. The trial enrolled 976 patients from 106 institutions in 20 countries. Accrual was over 5.5 years from November 1989 to July 1995.² The overall survival results from this trial are shown in Fig 1. Looking at the hazard ratio (HR) of 0.85 (95% confidence interval [CI], 0.71 to 1.02) in Fig 1, one can see that a 15% reduction in the risk of death was observed, which translated into a 3-year survival difference of 5.5% (50% in the no-chemotherapy arm and 55.5% in the chemotherapy arm). With a two-sided P value of .075, this difference was not conventionally statistically significant. The median length of follow-up for patients who were still alive was 4 years. These results therefore still are consistent with the possibility of no benefit for neoadjuvant chemotherapy. The improvement in 3-year survival may be anywhere from 0% to 11%, ranging from no benefit to a clinically important benefit in survival. To confirm this benefit reliably would require a trial of more than 3,000 patients (power, 90%; type I error, 5%).⁴ The SWOG trial is approximately one third the size of the International Intergroup trial, but it is of interest to note that survival curves of the two trials are very similar.

View larger version (28K): [in this window] [in a new window]   Fig 1. European Organization for the Research and Treatment of Cancer (EORTC)/Medical Research Council (MRC) overall survival. Reprinted with permission.2

Another trial that is very similar to the SWOG trial is the GUONE trial, in which 206 patients were accrued over a 6.5-year period.⁷ Although like the SWOG trial this is a small trial, no clear evidence of differences in survival were observed. The sample size was calculated to detect an improvement in 3-year overall survival of 15%, from 45% to 60%. Survival at 3 years was 62% for the MVAC arm and 68% for the cystectomy alone arm.

For the purpose of this presentation, we summarized the information from all relevant randomized trials in the form of a meta-analysis. This updates the systematic review performed by Parmar and Burdett¹⁷ by incorporating the GUONE and SWOG trial results (Fig 2). The log-rank "observed minus expected" (O–E) statistic and its variance were calculated when possible. Analyses were stratified by trial, and the log-rank expected and observed numbers of deaths were used to calculate individual and overall pooled HR. Thus, the time to death for individual patients was used to generate the HR, which represents the overall relative risk of a patient dying on treatment compared with the control arm. An HR of 1 indicates no difference between the treatment and control groups. An HR of less than 1 favors the chemotherapy group, and an HR of greater than 1 favors the no-chemotherapy group. The log-rank statistical analyses are then added together to provide an overall comparison of chemotherapy versus no chemotherapy. A black square in Fig 2 indicates the ratio of the death rates, as calculated from the log-rank statistics, and the horizontal line gives the corresponding 99% CI. The area of the square is proportional to the amount of information it represents. The variance, represented by the size of the black square, represents the amount of information each trial represents. The total number of deaths in a trial is approximately four times the variance, so the number of deaths also gives a measure of the amount of information. A study like the International Intergroup trial with 485 deaths has almost three times the amount of information as the SWOG trial. In Fig 2, where there is an "x" rather than a black square for a trial, this means that information to calculate the HR was not available for that trial and it therefore also does not contribute to the total. One can see easily that for every trial for which we have a summary result, including the SWOG trial, the CIs cross 1 (the equivalence line); therefore, no trial on its own is conclusive. For the overall combined value, the 95% CI is shown by the diamond. It seems that more favorable results are seen for cisplatin combinations than for trials with single-agent cisplatin. However, for both, the results are not clearly in favor of chemotherapy and trials of combination chemotherapy just approach the vertical line of equivalence where the HR is 1, giving a very borderline result in terms of conventional statistical significance.

View larger version (31K): [in this window] [in a new window]   Fig 2. Hazard ratios for overall survival in randomized studies of neoadjuvant treatment with cisplatin in patients with locally advanced bladder cancer.

In our opinion, the SWOG trial alone does not contain sufficient information or evidence to change medical practice. We also require more complete and reliable data than we were able to obtain from the published articles for our meta-analysis. Such an appropriate review and meta-analysis is under way.

IS NEOADJUVANT OR ADJUVANT CHEMOTHERAPY LIKELY TO BE MORE SUCCESSFUL?
There are two principal reasons to use neoadjuvant chemotherapy: (1) to improve survival in patients with micrometastatic disease and (2) to preserve the bladder.¹⁸ Bladder preservation was not really addressed in this trial because in all patients, cystectomy was planned.

The major disadvantages of neoadjuvant chemotherapy relate to the difficulties in assessing response in the primary tumour, because clinical rather than pathologic criteria are used. This means that we must base any early conclusions about the impact of neoadjuvant chemotherapy on results from the transurethral resection of the bladder (TURB), which can be misleading.¹⁹ More important, perhaps, precious time may be wasted before the most important component of treatment, the local therapy (cystectomy or radiotherapy) is instituted. Patients who do not respond to chemotherapy conceivably may become inoperable. In these patients, 3 months may be wasted on chemotherapy.

The rationale for giving adjuvant (rather than neoadjuvant) chemotherapy is that the local definitive and perhaps most important component of treatment is performed immediately. There is no delay in surgery, and no time is wasted, especially for patients who do not respond to chemotherapy. Treatment decisions are based on pathologic criteria, after careful examination of the cystectomy specimen. Micrometastases are treated when really at low volume.^20,21 With the advent of orthotopic bladder substitutions, most urologists tend to prefer upfront surgery.

Although a number of randomized trials have been performed, these trials of adjuvant cisplatin-containing combination chemotherapy have major deficiencies as a result of small sample sizes, early stopping of patient entry, statistical analyses, reporting of results, and reporting of questionable conclusions.²² Therefore, there are not sufficient data to suggest that even patients who are at high risk must be treated immediately rather than at the time of relapse.

On the basis of the desire to treat only patients who are at very high risk, the European Organization for Research and Treatment of Cancer together with the SWOG and many other international groups throughout the world has begun a very large trial of more than 1,300 patients, in the adjuvant setting, after cystectomy. This is a study to evaluate four cycles of immediate chemotherapy versus therapy at the time of relapse in high-risk patients with pT3 to pT4 or node-positive disease. Three different chemotherapy regimens will be permitted: MVAC, high-dose MVAC (HD-MVAC), and gemcitabine/cisplatin (GC).^23-25

The SWOG also is participating in another multicenter adjuvant study for patients with low-stage T1 to T2 tumors randomized after surgery to MVAC versus observation based on their p53 status.²⁶ New large-scale, multicenter adjuvant trials are imperative to providing convincing results of the true role of adjuvant chemotherapy.

WHAT IS THE BEST CHEMOTHERAPY TO TEST AND USE?
The European Organization for Research and Treatment of Cancer compared HD-MVAC plus granulocyte colony-stimulating factor with MVAC in a randomized trial of patients with metastatic bladder cancer. Although of modest size, this trial suggested an improvement in 2-year survival with HD-MVAC but, more important, less toxicity and the ability to administer chemotherapy in half the time. HD-MVAC was better in terms of progression-free survival (P = .037; HR, 0.75; 95% CI, 0.58 to 0.98), although not in overall survival as planned by the study (P = .122; HR, 0.80; 95% CI, 0.60 to 1.06). Patients who received HD-MVAC had a higher response rate (P = .06) and complete remission rate (P = .009) and a 25% less chance of recurrence or death than patients who were receiving MVAC (HR, 0.75; 95% CI, 0.58 to 0.98).²⁴ Another large randomized trial in patients with metastatic disease revealed that the combination of gemcitabine and cisplatin was less toxic than MVAC, with similar survival outcomes (P = .75; HR, 1.04; 95% CI, 0.82 to 1.32).²⁵

For these reasons, all of these chemotherapy regimens, together with CMV, are considered to be acceptable alternatives for the treatment of bladder cancer. Physicians seem to be selecting the one with which they feel the most comfortable.

CAN CHEMOTHERAPY CLEAR AND SPARE THE BLADDER?
Bladder preservation may be possible in highly selected cases but was not the subject of the SWOG trial, as all patients were planned to have a cystectomy. The pathologic complete response rate in the cystectomy specimen (pT0) in the SWOG trial was 38% in 48 of 126 patients who underwent MVAC and cystectomy. The pT0 rate in the International Intergroup trial in 417 patients who underwent surgery was 33% for patients who had CMV chemotherapy, but it was 12% for those who had TURB and cystectomy alone without chemotherapy. The SWOG investigators showed that patients who respond to chemotherapy do well. It is clear that response to chemotherapy is an important prognostic factor. This has been shown in this Intergroup study and by others.^27-29 Although interesting, it must be stressed that it is widely known that this type of analysis is flawed and it could be that the patients who do well have certain characteristics that would make them survive longer anyway.

Response to MVAC chemotherapy is an important prognostic factor, but is this justification to treat everyone? The clinical stage underestimates the pathologic stage in up to 36% of patients who undergo TURB after MVAC before cystectomy. With long-term follow-up, only one third of patients actually have their bladder preserved.²⁸ If we are considering bladder sparing as a major outcome, then we need to ask questions such as, "Is it worthwhile to give potentially highly toxic chemotherapy to the two thirds of patients who do not benefit or whose bladder is not preserved?"

WHAT IS CURRENT BEST STANDARD TREATMENT?
The SWOG investigators concluded that this is the first randomized clinical trial to "demonstrate a statistically significant and clinically meaningful improvement in survival with neoadjuvant chemotherapy." As we argued above, there are many reasons not to accept this statement, not the least of which is that using two-sided testing (as nearly all of the other trials have done), the results of the SWOG trial are not conventionally statistically significant. There is no doubt that the results of the SWOG study are interesting but perhaps not as significant as the investigators would like to believe or have us believe. An important point to consider is that changing medical practice on the basis of a small trial that had an 11-year accrual period and only 90 deaths in one arm and 96 deaths in the other arm has considerable methodologic problems. The SWOG investigators suggest that three cycles of MVAC chemotherapy should become a standard therapy. It should be noted that three cycles is empiric, GC may be less toxic, and HD-MVAC can be given in a shorter time period. Furthermore, MVAC and CMV have never been compared. The pT0 rate is similar, suggesting similar efficacy. MVAC easily can be given before radical cystectomy in patients with locally advanced bladder cancer; however, MVAC chemotherapy is toxic, especially as it was given in this study, without growth factors, now considered standard therapy. A 7% rate of grade 3 to 4 granulocytopenia was observed.

Publication bias is very prevalent in oncology, and studies are more likely to be quoted and published widely when they are positive or when they are large.^30,31 For example, it may be useful to consider that if the SWOG trial had not been described as a conventionally significant trial, then there is a very strong likelihood that it would not have been the subject of the ASCO plenary session and we would not be discussing it in such detail here.

In our opinion, this trial on its own cannot change clinical practice and must be taken in context with evidence from all of the other relevant randomized trials.

In conclusion, there are many unanswered questions in the management of muscle-invasive bladder cancer. Is immediate chemotherapy needed in all patients, or can we wait until relapse? Are we overtreating patients who do not need or benefit from such therapy? Which chemotherapy regimen is the best? Was CMV the correct regimen in the International Intergroup trial? Should we be using MVAC, HD-MVAC, or GC? Is doxorubicin necessary in MVAC? Can molecular markers such as p53 guide our choices? What is the best way to administer chemotherapy: in the neoadjuvant or the adjuvant setting? Finally, can similar results be achieved with an adjuvant protocol that might spare some patients chemotherapy?

The SWOG Intergroup trial accounts for 10% of all patients randomized onto trials of neoadjuvant chemotherapy. On the basis of the currently available data from all trials included in our review, we cannot be sure of the value of neoadjuvant chemotherapy. The individual patient data meta-analysis being conducted by the Medical Research Council might give a clearer answer (in either direction). Furthermore, it is hoped that the international adjuvant chemotherapy trial will determine whether adjuvant chemotherapy is beneficial and, if so, whether we can spare some patients unnecessary chemotherapy.

ACKNOWLEDGMENT
This portion of the ASCO plenary session was a tribute to Alan Yagoda, MD (Fig 3), who developed the MVAC chemotherapy regimen and trained all of the speakers and participants in this debate. We all miss him dearly.

View larger version (102K): [in this window] [in a new window]   Fig 3. Dr. Alan Yagoda.

	REFERENCES

TOP INTRODUCTION HOW SHOULD WE INTERPRET... REFERENCES

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4. Machin D, Campbell MJ, Fayers PM, et al: Sample Size Tables for Clinical Studies. London, United Kingdom, Blackwell, 1997

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6. Malmstrom PU, Rintala E, Wahlqvist R, et al: Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy. J Urol 155: 1903-1906, 1996[Medline]

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8. Crawford ED, Natale RB, Burton H, et al: Southwest Oncology Group Study 8710: Trial of cystectomy alone versus neo-adjuvant M-VAC and cystectomy in patients with locally advanced bladder cancer (Intergroup trial 0080), in Splinter TAW, Scher HI (eds): Neoadjuvant Chemotherapy in Invasive Bladder Cancer: Progress in Clinical and Biological Research. New York, NY, Wiley-Liss, 1990, pp 111-113

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17. Parmar MKB, Burdett S: Neoadjuvant and adjuvant chemotherapy, in Hall RH (ed): Clinical Management of Bladder Cancer. London, United Kingdom, Arnold, 1999, pp 249-263

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24. Sternberg CN, de Mulder PHM, Schornagel JH, et al: Randomized phase III trial of high–dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924. J Clin Oncol 19: 2638-2646, 2001[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sternberg, C. N. Articles by Parmar, M. K.B. Search for Related Content PubMed PubMed Citation Articles by Sternberg, C. N. Articles by Parmar, M. K.B. Social Bookmarking                            What's this?