Author's response to reviews Title: Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA-CA15.3 panel in the early detection of distant metastases. Authors: Andrea Nicolini (a.nicolini@int.med.unipi.it) Gianna Tartarelli (a.nicolini@int.med.unipi.it) Angelo Carpi (a.nicolini@int.med.unipi.it) Maria Rita Metelli (a.nicolini@int.med.unipi.it) Paola Ferrari (a.nicolini@int.med.unipi.it) Loretta Anselmi (a.nicolini@int.med.unipi.it) Massimo Conte (a.nicolini@int.med.unipi.it) Piero Berti (a.nicolini@int.med.unipi.it) Paolo Miccoli (a.nicolini@int.med.unipi.it) Version: 4 Date: 26 June 2006 see over Author's response to reviews:
Author s response to reviews Title: Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA-CA15.3 panel in the early detection of distant metastases. Authors: Version 2 Date 22-06-06
2 The Biomed Central Editorial Team Object: MS 1043615023846295 - Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA- CA15.3 panel in the early detection of distant metastases. Dr Andrea Nicolini et al. Thank you for consideration of our manuscript for publication in your Journal. We have reviewed the above manuscript according to your reviewers comments. Reviewer 1 (Dr Cheung) Major compulsory revisions 1) Clarify when markers were elevated (with re-testing), all patients were clinically disease-free, and if yes, whether radiological investigations were carried out at the same time to establish the presence/absence of metastases. Otherwise the calculation of lead time would not have been accurate. 1) When a clinically disease-free patient was suspected of relapse by re-testing of tumour markers at the regular control visit, 15 to 30 days were necessary to carry out the common (bone scintigraphy, liver echography, chest x-ray) and in case of their equivocal result, more accurate radiological examinations (CT, MRI) to confirm or rule out the suspicion. During this relatively short interval time, the clinical condition of all suspected patients remained substantially unchanged. Moreover, radiological investigations performed during this 15 to 30 days interval time and confirming the initial suspicion by tumour markers were considered as they had been performed at the same time of tumour marker re-testing; therefore in this case tumour marker lead time was computed as zero. (See Methods, Tumour markers section, page 5, lines 27-34). 2) Clarify if radiological investigations were carried out when a patient became symptomatically suspicious of metastases, before the routine testing of serum tumour markers. And if the tests were positive, clarify whether markers were measured, as this again would have affected the calculation of lead time.
2) When a patient became suspected of metastases by symptoms before the routine testing of serum tumour markers (i.e. in the interval between two regular control visits), at this time immediately the entire planned procedure was carried out to confirm or rule out the suspicion. Therefore two blood samples (at two weeks interval time) were withdrawn and the common (bone scintigraphy, liver echography, chest x-ray) and, in case of equivocal result, the more accurate radiological examinations (CT, MRI) were performed to confirm or rule out the suspicion. As above mentioned, the time necessary for the entire procedure took about 15 to 30 days and this interval time was not considered for the calculation of the tumour marker lead time. In fact, when suspicion of metastases was confirmed by radiological examinations and not by tumour marker panel, tumour marker panel was considered falsely negative. When suspicion of metastases was confirmed by radiological examinations and by tumour marker panel as well, the tumour marker panel lead time was considered zero if symptoms suspicious of metastases had appeared at the same time the entire procedure for confirmation was started; if symptoms suspicious of metastases had previously appeared, clinical symptoms only were considered the first signal of relapse and tumour marker panel was considered falsely negative. (See Methods, Tumour markers section, page 5, last line and page 6, lines 1-13) 3 Minor essential revisions 1) Typo error page 4, par 4: first sentence incomplete; par 5 and 6 repeated. 1) Typo errors, page 4, paragraph 4: first sentence has been completed. (See Methods, Patients follow-up section, page 4, lines 26-28). Fifth and 6 th paragraph repeated: one of the two paragraphs has been deleted. (See Methods, Patients follow-up section, page 5, lines 3-4). Discretionary revisions 1)Can the authors clarify if outside the context of a study, it is routine practice in their centre to carry out intensive follow-up using both serum markers and imaging for post-surgical breast cancer patients, as described in the paper? 1) Yes, it is routine practice in our Center to carry out intensive follow-up using both serum markers and imaging for post-surgical breast cancer patients. (See Background section, page 3, lines 7-9).
2) Suggest shortening the text for the Results section, by using more tables and deleting some of the details. 4 2) As requested by reviewer 3 as well, the Result section has been shortened deleting many details shown in the Tables. (See Results section, page 7, lines 16 and 27, page 8, lines 11 and 20, page 10, lines 17-29) Reviewer 2 (Dr Dixon) General 1) Measuring tumour markers is controversial. It is costly and the problem is that early detection of metastatic disease has not been shown to influence outcome. 1) As general remark, the reviewer first writes that measuring tumour markers is costly and early detection of metastatic disease has not been shown to influence outcome. Also he adds that measuring tumour markers is controversial. This last sentence is in contrast with the previous one. In fact, if studies on serum tumour markers to post-operatively follow-up breast cancer patients had clearly shown unfavourable cost/benefit ratio, neither their use for this purpose should be so controversial, nor so many studies on this issue would continue to be published. Indeed as far as we know, only two multicenter prospective randomized trials explored by an intensive post-operative follow-up the influence of an early detection of metastatic disease on the final outcome. Results of both these trials were published in the nineties and they did not show any benefit from an early detection of recurrences. Nevertheless in both trials clinical instrumental was compared with clinical only follow-up and neither any serum tumour marker panel nor appropriate criteria for its use were adopted (see references 2-3). Different studies appropriately using serum tumour markers within an intensive post-operative follow-up showed that in many relapsing patients clinicalinstrumental diagnosis was anticipated and that this anticipation permitted an earlier treatment which significantly prolonged DFS and/or OS (see references 7-9). These favourable although limited results support the hypothesis that in breast cancer patients an early detection of relapse with serum tumour markers can significantly ameliorate clinical outcome and rise the need for large prospective randomized trials with an appropriate use of them. These trials have been proposed by many investigators but as far as we know so far no result has been published. Therefore, the
statement of the reviewer early detection of metastatic disease has not been shown to influence outcome is not appropriate. (See Background section, page 2, last line and page 3, lines 1-6) 5 2) Follow-up was 16 months. They did close to a 1000 bloods to detect 18 distant recurrences and measured 4 tumour markers. These markers picked up at most 74% of recurrence and had positive predictive value of 56% i.e. 4/10 are false positives. There was a lead time of 5 months. These results finally show that measuring tumour markers is a complete waste of time and money. To put any other gloss on these data is inappropriate. In its present form it is unpublishable because it does not deal with the real issue why should anybody who has seen these results think tumour markers are worthwile? 2) The remaining general remark is a comment to the results of the submitted study. He writes that from these results a reader deduces that measuring tumour marker is a complete waste of time and money. We believe that this so unfavourable opinion does not reflect the presented data because of the following reasons: a) As highlighted in the title, all recurrences early detected in the study were distant metastases because the principal scope for the use of tumour marker panel is to early detect distant metastases rather than locoregional recurrences. In fact locoregional recurrence usually is early detected by physical examination only and often it is amenable for a locally radical curative intervention by surgery and/or radiation. b) Disease confined to bony skeleton is considered a favourable prognostic factor for the relatively longer survival (see references 32-33). c) A recent trial showed that a single lesion i.e., minimal metastatic disease amenable to local therapy also called stage IV oligometastatic disease is a particular condition with very relatively favourable prognosis when treated with local intervention (surgery and/or radiation) followed by high dose chemotherapy. In the same study authors concluded that the reported results implied the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit. Moreover, in an editorial devoted to comment this trial and published in the same issue, whether limited metastatic breast cancer can be cured is questioned (see references 34-35). d) In these selected metastatic patients with oligometastatic disease or limited to bony skeleton median OS 2-3 times longer than in general metastatic population and up to 62% five years OS have been reported. e) In the submitted study, as summarised by the reviewer, 14 (74%) of 19 recurrences (all distant metastases) were detected with our follow-up using CEA-TPA-CA15-3 tumour marker panel with about 5 months as mean lead time. Eight (42%) of these 14 recurrences presented as oligometastatic
disease (5) or disease confined to bony skeleton (3). Therefore, in about 40% of the patients who relapsed during our intensive follow-up using CEA-TPA-CA15.3 panel, median survival 2-3 times longer than that of general metastatic population could be expected and some oligometastatic patients, if appropriately treated, could be definitely cured. f) At this moment, CEA-TPA-CA15.3 determination from a blood sample costs to our Health Service about 45 Euro, so that the cost of the entire CEA-TPA-CA15.3 follow-up in this study was 45,000 Euro. Therefore, the final question is whether 2 or 3 times more median overall survival in about 40% of relapsing patients from an initial population of 268 subjects and providing some of them of the possibility to be definitely cured is enough to charge the Health Service with the above reported expenses. We are not so sure that any reader considering the pros and cons on the issue would share with the reviewer that results of our study finally show that measuring tumour markers is a complete waste of time and money. (The issue e has been reported in Results section, page 8, lines 20-23; the issues a-b-c-d have been discussed in Discussion section, page 11, lines 31-34, page 12, lines 1-8 and also reminded in Conclusions, page 12, lines 18-21). 6 Reviewer 3 (Dr Torrisi) General 1) Background: Authors should point out that the routine use of any instrumental or lab test, except of mammography is not recommended since it has been shown to be useful only in early diagnosis but not in improving clinical outcome and/or quality of life in randomised trials and meta-analysis. 1) Background section: it has been pointed out that the routine use of any instrumental or lab test, except of mammography, is not recommended since it has been shown to be useful only in early diagnosis but not in improving clinical outcome and/or quality of life in randomised trials and metaanalysis. (See page 2, lines 30-34). 2) Methods: it is not clear why authors considered only nodal and progesterone receptor status and not other variables to divide patients in intermediate risk and low risk. 2) Methods section: axillary lymph-nodes (N+/N-) and progesterone (PgR+/PgR-) status were used to divide patients into two different risk groups as they are commonly reported among the principal
prognostic factors for relapse. This explanation was added (see Methods section, subheading entitled Patients follow-up, page 4, lines 9-12). 7 3) In addition there is no further mention whether results observed were similar or different in these two populations. 3) No further mention was made whether results were similar or different in these two populations because, as expected, it was observed a higher rate of relapse in patients N+ and/or PgR- versus those N- and PgR+ and no significant difference of the studied parameters occurred in these two different populations. Therefore, these findings were not reported in the study. 4) Moreover no information is provided whether these patients had received or were receiving adjuvant treatment. 4) The information on adjuvant treatment has been added in the text (see Methods section, subheading entitled Patients follow-up, page 4, lines 4-7). 5) No clear explanation on the timing of clinical imaging used to verify a progressive elevated tumour marker is provided. Which is the reason for performing bone scintigraphy and liver echography at 24-30 month and CXR at 42 month interval? Authors should clarify. 5) As now reported patients suspected of relapse with CEA-TPA-CA15.3 tumour marker panel immediately underwent the standard radiological examinations (bone scintigraphy, liver echography and chest x-ray). If they were pathological or equivocal, patients immediately were selected to be further investigated with more accurate radiological exams (CT, MRI) or cytologic study. (See Methods section, subheading entitled Patients follow-up, page 4, lines 25-28). As bone scintigraphy and liver echography have been reported to be more accurate than chest x-ray to early detect recurrences, they were regularly carried out at shorter interval. (See Methods section, subheading entitled Patients follow-up, page 4, lines 17-21). 6) Discussion: It should be thoroughly revised since it mostly contains data that have been reported either in the Results section and in the Table. The authors should provide an interpretation of their findings and expand the reasons to support the scientific and clinical relevance of their findings.
6) Discussion section: discussion has been thoroughly revised and most data reported either in the Results section and in the Tables have been deleted. (See answer to Reviewer 2, discretionary revision, question 2). Besides, an interpretation of the study findings and an expansion of the reasons to support the scientific and clinical relevance of these findings have been provided. (See Discussion, page 11, lines 31-34 and page 12, lines 1-8 (this paragraph has been added) and Conclusions, page 12, lines 18-21). 8 7) Page 4: Verify the editing (a truncated sentence is reported in line 13 and at the end of the 1 st paragraph a sentence is reported twice). 7) Page 4: the truncated sentence has been completed (See Methods, Patients follow-up section, page 4, lines 26-28) and at the end of the first paragraph one of the repeated sentences has been deleted. (See Methods, Patients follow-up section, page 5, lines 3-4). 8) Table 3 is redundant since it is reproduced in its whole in the text (page 9) so it can be omitted or alternatively do not provide all numbers in the text. As to Table 3, all numbers referring to this table have been deleted in the text. (See Results section, page 10, lines 17-29).