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Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on thebmj.com. Although a selection of rapid responses will be included online and in print as readers' letters, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window. Letters are indexed in PubMed.

Re: Comparison of postoperative outcomes among patients treated by male and female surgeons: a population based matched cohort study Allan S Detsky, Raj Satkunasivam, et al. 359:doi 10.1136/bmj.j4366

Firstly I would like to thank the authors for writing this stimulating article. I have a few general comments and some critique.

By stipulating that “the care provided by an inpatient internal medicine service is performed by a team” and “by contrast … the primary surgeon has a direct effect on patient outcomes” could be seen to infer that surgery is not a team effort. Which is of course not true. In fact in training hospitals the primary surgeon may be overseeing or supervising a junior colleague carrying out the majority of the procedure. More senior trainees are often responsible for opening and closing with the surgeon of record on site but unscrubbed. So the surgeon of record for analysis may not have performed the entire operation from start to finish.

I am critical of the exclusion of the 8753 patients treated by physicians whose primary declared specialty was non-surgical. I am unfamiliar with how the primary specialty is declared in Canada. However, if the declaration is in any way similar to in the UK this could exclude a vast number of cancer patients. The primary specialty is often the physician overseeing the multidisciplinary team meeting at the time of initial diagnosis, such as haematology, oncology, respiratory medicine, gastroenterology and many more. This exclusion has the potential to augment results relating to all outcome measures given the morbidity and mortality associated with malignancy. There is no mention in the limitations of the large number of patients excluded because the treating institution could not be identified. Allowing for the other exclusions this represents 4.47% of the true sample size and could contain significant data pertinent to the results.

This article contributes to a growing body of observational research into sex and gender issues in the wider medical field. I think it’s important that the authors acknowledged that they were unable to identify transgender surgeons, given that they used biological sex at the time of registration as means of categorisation. Accepting this study limitation, it is possible that trans female surgeons are being analysed within the male group and trans males in the female group. The authors state “female and male physicians differ in their practice of medicine” with “female doctors being more likely to use a patient centred approach and to follow evidence based guidelines”. Given that there is more than just biological determinism of gender, the practice and approach of trans surgeons may differ significantly from their natal sex and align more with their gender. I concede that transgender surgeons who transitioned since registration are likely to represent an incredibly small proportion of this cohort. However, it is my belief that transgender surgeons’ outcomes should be analysed within the category of their self-assigned gender. To analyse them within their natal sex group is to potentially underestimate the results.

Competing interests: No competing interests

13 October 2017
Josephine C Weaver
Junior Doctor
Melbourne, Australia
Re: Do cancer drugs improve survival or quality of life? Vinay Prasad. 359:doi 10.1136/bmj.j4528

As I am bound still by some level of confidentiality and despite semi-retirement and my remote location, I tend to support this authors thesis wholeheartedly (although my experience dates back to 2004 and earlier). Before that I spent a a lifetime in Medicines Development and Regulation in Europe including many oncological therapeutic agents - including chemotherapy and biological agents such as monoclonals, DNA vaccines and Gene Therapies. The latter two at that time were the most promising but not necessarily safe. Many conventional chemical anticancer drugs are extremely toxic with a wafer thin therapeutic margin with often rather theoretical mechanisms of action. One area I found particularly questionable was the first use of new chemical entities and viral vector in Phase I studies in what might be casually referred to as 'no hope' patients with cancer. The studies were much more about establishing the level of toxicity (safety) than giving the assessor any hope of benefit, yet the consent forms presented hope was offered when there was none of scientific credibility. If I should get terminal cancer I will go no-where near a Phase I study and thereafter I will evaluate if am able the evidence before ANY agent is given to me. If I am unconvinced I will refuse.

Both my mother and father developed colon cancer. My mother was offered firstly experimental surgery (2008) and when we refused, simply diagnostic laparotomy (no laparoscopy offered then). On discovering widespread peritoneal metastases she then required a defunctioning colostomy and was offered rectal radiotherapy - where the benefits were at best dubious and the toxicity undoubtedly significant - on the basis that she might live 6 weeks. We refused on that basis and she lived a fairly happy life for over 3 years eventually dying from later medical mismanagement of a benign condition (pain from an obstructed bladder other than cancer). My father on the other hand alas then perished in 2006 from palliative care he did not need. We have hopefully travelled some way since that time but I would suspect very little and this author confirms this. Whereas we might reference chemotherapies in childhood leukaemia as breakthroughs even here the approach of using differential poisoning is the nearest lay term I can use.

Adjuvants in breast cancer have also played an important part in treatment. The development of modern monoclonal antibodies is also more heartening because of lower levels of toxicity. But still their benefits are often hugely overstated and limited to subsections of patients we can hardly define. As most therapeutics are designed by commercial developers to be 'blockbusters' or highly 'prestigious' agents - and therefore unbelievably expensive for limited QOL, or even life extension. Such research teams approach therapeutic interventions by focusing primarily on commercial success rather than exploratory science. Well that is their modus operandi. Like many established medicines, we largely need to understand the ones we've got rather than the ones we may get. We use these often quite poorly. Patient's understand them even less. There are no magic bullets for anything. There is only greater understanding. And then from the burgeoning population we will create there will be new dilemmas for the planet - aged care and increasing dementia. If we could develop as a profession a more universal palliative approach to many of the cancers we see - following the simple principles of caring, reassuring, counselling and supporting - we might well do more good than ill and accept that life can be short but it is lived to the full.

Competing interests: Former regulator of Clinical Trials and New Medicines, former Consultant and Executive Director of Medicines Development - various organisations.

13 October 2017
Philip James Harrison
General Practitioner
HUTT CITY HEALTH CENTRES - recently semi-retired
Wellington, New Zealand
Re: David Oliver: How much information should patients’ families expect on acute wards? David Oliver. 359:doi 10.1136/bmj.j4295

Thank you David Oliver for being that person who stands up to say openly what so many are only willing or confident to say behind closed doors.

I remember many evenings and weekends on call as a junior doctor being accosted by eager relatives wanting to know exactly what happened, when, why, and what happens next. Or paged by nurses saying Mrs Z's 3rd cousin has just arrived from Australia and wants to know what's happening. With 20 jobs to do and half a hospital to look after, faced with trying to decipher and then translate the notes of a patient I have never met to ease the guilt-driven anxiety of a prodigal relative, cognitive overload kicks in.

Cold common sense says there is no urgency, I am not the right person to have this conversation, this could be a breach of confidentiality. But inexperience, stress, tiredness, and youthful eagerness to soothe anxious relatives' need for reassurance, leaves young doctors vulnerable. With experience I have come to realise that such conversations with distanced relatives are unnecessary, even harmful. With practice and confidence I can defer to the patient, close relatives/carers, nurses who know what is happening.

There are so many things wrong with the above scenario- work over-load, inappropriate task delegation and bullying, professional self-derogation (why make the FY1 do what the nurse is better placed to do?), and lack of leadership to prepare and support staff for recurrent events. And all this does is perpetuate the unrealistic expectations for endless repeats of information, and denegration of the nursing profession

But on the other hand, relatives deserve compassion, understanding. There is (in most cases) no intent to add to the doctor's stress, or put them on the spot. They just want to know what's happening, what does it mean. What is needed is clear information on the wards to indicate how to get information and duties of confidentiality; nursing staff actively encouraged to use the voices they have as patient advocates and healthcare professionals; and leadership to direct and promote staff support, clear boundaries and realistic expectations.

Communicating with patients is a double-edged sword, but compassion and realism can cut through the suffering of both anxious relatives and tired, stressed doctors.

Competing interests: No competing interests

12 October 2017
Cathy Welch
GP
Arran Medical Group
Re: General practice threatens to withhold repeat prescriptions until patients have flu vaccine Gareth Iacobucci. 359:doi 10.1136/bmj.j4682

Assuming the headline is correct, the GPs concerned were acting unlawfully. They did not seek informed consent. They just demanded that jabs be accepted.

Here is a suggestion. Please give ALL general practitioners a respectable per capita yearly allowance and abolish fee per immunisation, per IUCD, per condom prescription, per every other procedure. Bin the Quality Outcome nonsense.

Here is a challenge. Pay a doctor (hospital or private or NHS GP) a fee for notifying every side-effect of any drug, including imm and vacc products.

I have a hunch that we will see medicine practised with greater conscientiousness.

Competing interests: No competing interests

12 October 2017
JK Anand
Retired doctor
Free spirit
Peterborough
Re: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13 Ashlyn Pinto, Ajay Aggarwal, et al. 359:doi 10.1136/bmj.j4530

The high price of new cancer drugs has fuelled a debate on their added value and the evidentiary standards for regulatory approval. The findings by Davis et al. (BMJ 2017;359:j4530) that several cancer drugs entered the European market without clear evidence of extending duration of survival or improving quality of life (QoL) are not surprising to anyone familiar with cancer drug development. It is well known that in many situations demonstrating a clear effect on survival or QoL is not feasible and a benefit can be shown on the basis of other endpoints. There are several reasons for this.

First, there are good reasons why an effect on overall survival may be difficult to detect, such as when control-group patients in a randomized clinical trial (RCT) switch to the experimental treatment after progression, or when multiple subsequent lines of effective treatments “dilute” the effect of a drug used in earlier lines. In these and other situations, progression-free survival (PFS, the time during which treatment can induce and maintain a response or at least delay the growth of cancer) has been the efficacy outcome on which many cancer drugs have been approved; the justification being that (if of sufficient duration, with acceptable toxicity and no detriment in overall survival) prolonging PFS will delay onset and worsening of symptoms. Importantly, if a sufficient effect is observed based on this endpoint, it is generally considered to reflect an intrinsic clinical benefit and is not a “surrogate” for survival requiring subsequent confirmation, as Davis et al. seem to imply.(1,2,3)

Second, when “dramatic activity” is observed in terms of objective response (tumour shrinkage) and response duration on the basis of single-arm trials in a well-defined patient population with high unmet medical need, RCTs are considered unethical or unfeasible and “early approval” mechanisms can be used. This applies to a minority of cases and requires that the course of the disease is highly predictable, that there are no good therapeutic alternatives and that there are sufficient supportive clinical and non-clinical data to show a positive benefit-risk balance. Confirmatory data on long-term endpoints are generally requested in these situations, although the evidence may sometimes be extrapolated from related indications when direct confirmation in the same indication is not possible (e.g., when RCTs are not well underway at the time of approval).

Third, QoL is often difficult to assess for a number of reasons, including when double-blind trials cannot be conducted because the distinct toxicity profiles of drugs make them difficult to mask, or there is poor compliance with questionnaire completion. Drawing conclusions on the basis of single items or domains of a QoL instrument is also generally challenging due to the risk of chance findings. Therefore, QoL is rarely used as the primary efficacy endpoint in cancer clinical trials and convincing clinical benefits in terms of QoL are only rarely shown. This, however, does not mean that EMA does not value such studies, which are encouraged even if often they do not lead to robust conclusions. (1,4)

Lastly, there are indeed situations when drugs are approved on the basis of small incremental benefits instead of giant leaps, which are relatively rare. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used by Davies et al. to identify drugs that bring a clinically meaningful benefit has its limitations including failure to recognise small incremental benefits. This scale was never designed for the purpose of clinical decision-making and was mainly constructed on the basis of oncologists’ views rather than a systematic evaluation of patient preferences. Patients play a key role in informing value judgments of benefits and risks of treatments, and EMA has been active over the years in implementing its framework for patient involvement in benefit-risk assessment.

A detailed discussion of the examples mentioned in the article, as well as a response to the claim that “EMA has either failed to identify or overlooked” methodological problems made in the accompanying Feature (doi:10.1136/bmj.j4543), is not possible here. It suffices to say that approval is not a ruling on drug development or whether the ideal trial designs, comparators and methods of analysis have been used, but a scientific conclusion on the balance of the benefits and risks based on available data. Thus, the conduct of trials according to the most rigorous methodology is strongly encouraged whenever possible but in general is not a pre-requisite for approval provided that existing uncertainties can be addressed on the basis of the totality of the data, including future studies, where appropriate.(5) For every assessment, EMA publishes on its website all the details about the data submitted, benefit-risk assessment evaluations, remaining uncertainties and how they were handled, and justifications of any deviations from standard methodology in the context of the available evidence and therapeutic context.

We all strive to help patients live better and longer. However, restricting approvals of cancer drugs only to situations where there is indisputable evidence of improvement in survival or QoL will not improve the lives of cancer patients. On the contrary, such an approach may deprive patients in urgent need of early access to effective medicines. In such situations, early access to new drugs that fulfil an unmet medical need has to take precedence over generating evidence according to the highest standards for health economic evaluation. Science and standards are here to serve patients and not the other way round.

References
1. European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in man. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin....
2. Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 2008;13 Suppl 2:19-21.
3. European Medicines Agency. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man - methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin....
4. European Medicines Agency. Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man: The use of patient-reported outcome (PRO) measures in oncology studies. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/04/WC500....
5. Jonsson B, Bergh J. Hurdles in anticancer drug development from a regulatory perspective. Nat Rev Clin Oncol 2012;9(4):236-43.

Competing interests: No competing interests

12 October 2017
Francesco Pignatti
Head of Oncology, Haematology and Diagnostics
European Medicines Agency
30 Churchill Place, Canary Wharf, London E14 5EU, United Kingdom
Re: Is gabapentin effective for women with unexplained chronic pelvic pain? Andrew W Horne, Katy Vincent, Roman Cregg, Jane Daniels. 358:doi 10.1136/bmj.j3520

One could argue that medicating medically undiagnosed symptoms (MUS) is a little like practicing surgery in the dark; it disempowers both practitioners and patients alike. An alternative way of considering chronic pelvic pain is to reconsider the personal as a whole entity for whom emotional pain is manifesting in the body as a consequence of denied, buried or unmanaged emotional pain, and assessing symptoms on a biopsychosocial model.

“[Emotional] pain demands to be felt” ; and if we don’t explore the possibility that chronic pain may have underlying emotional roots then the bill for treating medically unexplained symptoms and consequences of emotional distress with medication and surgery will continue to soar. It is surely counter intuitive to medicate the symptoms of conditions of unknown cause, where there is now a large volume of academic literature supporting the cause for looking at “what lies beneath” as a way of following a bread crumb trail back to the original source of [emotional] pain, allowing for the possibility of real and long lasting treatment. This approach requires a whole person conversation that doesn’t seek to focus solely on the woman’s pelvis, or a single moment in time, but assess her whole being, and the whole life that has led her to this point.

Competing interests: No competing interests

12 October 2017
Rachel Preston
GP
Abi Finnegan
Lakes Medical Practice
Re: Data, data everywhere: the challenges of personalised medicine Stephen Armstrong. 359:doi 10.1136/bmj.j4546

"Can public trust in health record sharing be regained?", Armstrong asks.

It would be much easier if we knew the data was held for health sector uses such as planning services, and for patient benefit only - as used to be the case.

The government has driven a coach and horses through this principle, with a memorandum of understanding between NHS Digital and the Home Office, in a way which it would put a doctor before a GMC service committee.

This will make it far harder for patients to trust that their information will not be (mis)used, to their disadvantage.

(For more information - I have blogged about this at http://peterenglish.blogspot.co.uk/2017/02/home-office-mou-to-access-nhs... , or visit the Doctors of the World web site https://www.doctorsoftheworld.org.uk/.)

Competing interests: No competing interests

12 October 2017
Peter Mark English
Public Health Physician
N/A - this is a personal response
Epsom
Re: Evaluation of telephone first approach to demand management in English general practice: observational study Marc Elliott, Josephine Exley, Adam Martin, Catherine Saunders, et al. 358:doi 10.1136/bmj.j4197

This study has been widely reported as showing that telephone-first GP triage doesn't work. This interpretation is only valid if the questions the study failed to ask are ignored.

Some news sources reporting this study used headlines that were, in context, reasonable "Phone-first GP consults 'no panacea for reducing workload' (eg http://ct.moreover.com/?a=31981498170&p=1pl&v=1&x=0VZh2oPqbuCUQmJO_ZG4jQ) is a common phrasing and technically accurate even when the tone of the report itself is mostly negative. "Offering phone consultations as standard could increase GP workload" (see http://ct.moreover.com/?a=31977777830&p=1pl&v=1&x=DCJM9g3LznUWixkRF2YF4g) is slanted towards the negative but could be considered technically accurate. Most of the news reports tended towards skepticism that telephone-triage works in ways that were more negative than the headline. But the tone of most reports miss an important fact reported in the research: the variability of the results.

The research understates the significance of the large degree of variation in the results and fails to ask the obvious question: "why do some practices see large reduction in GP workload when others do not". In fact it would be equally valid to rewrite the negative Pulse headline as "Offering phone consultations as standard could DECREASE GP workload" as that is what the results say.

The BMJ editorial headline is relatively balanced "Policy makers should reconsider their unequivocal support for these systems" but also failed to ask the obvious question about why some practices saw large benefits and others did not. There is no point in either recommending an intervention unequivocally or condemning it as ineffective when you don't know why it sometimes works and sometimes does not.

I have a theory that might help with future research but would also help temper the negative reporting of the study. Telephone-first triage only works well if you manage it well.

Two factors matter a lot if the GP is to gain any benefit from lower workload. One is the length of the typical phone call (it needs to be much shorter than a face-to-face consultation. The other is the proportion of calls that need a face-to-face follow up. These are both strongly dependent on the skill of the GP (skilled practitioners have short calls and few follow-ups). While it is true that some patients need more time than others it is likely that, all other things being equal, a skilled GP will have much shorter calls and fewer follow-ups. A well-managed practice will monitor these metrics (as well as some quality metrics to ensure time isn't traded for poor quality decisions) and will optimise them over time.

This implies that phone-first triage by itself is not an effective tool for anything but that phone-triage plus competent management processes can yield big improvements. The study ignored this factor (or lumped it into the "more research needed" category). It also shows that lumping together the results by reporting the average across all participants is misleading (this is how the negative headlines are derived). A more accurate headline would be "some practices see big benefits while others do not".

It is also worth noting that some of the conclusions are very dependent on dubious data about GP workload. The largest supplier of GP clinical systems does not routinely report how long telephone-calls take making it essentially impossible to judge whether a system using many calls saves GP time or not. The second largest vendor can report this, but local setups often prevent the data being reliable. If GPs are to operate a phone-first process effectively they need to be able to record the length of calls reliably.

In short we should not dismiss telephone-first triage as a failure. Nor should we accept it as a magic-bullet. We should pursue an better understanding of why it sometimes yields large benefits and sometimes doesn't.

Competing interests: I provide analysis services to GP Access, one of the firms participating in the work described in the paper (though I was not involved in the study and was not providing services at the time it was completed).

12 October 2017
stephen black
data scientist
black box data science
biggleswade, bedfordshire
Re: Domestic violence is poorly covered in medical training, study finds Abi Rimmer. 359:doi 10.1136/bmj.j4646

Economic impact of domestic violence should greatly alarm politicians and healthcare managers, inducing prioritized interventions.
Domestic violence costs $8,000,000,000,000 annually! [1][2][3]
In comparison, the total cost of all new cases of cancer worldwide in 2010 was only $290 billion. [4-page 35-Box 11]
References
[1] https://www.weforum.org/agenda/2014/09/domestic-violence-cost-war-develo...
[2] http://www.huffingtonpost.com/bjorn-lomborg/domestic-violence-8-trillion...
[3] http://www.reuters.com/article/us-abuse-costs-idUSKBN0H41AL20140909
[4] http://apps.who.int/medicinedocs/documents/s18806en/s18806en.pdf

Competing interests: No competing interests

12 October 2017
Stavros Saripanidis
Consultant in Obstetrics and Gynaecology
Hellas
Re: Sperm counts, testicular cancers, and the environment Niels E Skakkebaek. 359:doi 10.1136/bmj.j4517

This is a provocative piece by the editor. It has been well flagged in the aquatic kingdom also. The feminization of male fish and other aquatic animals such as alligators turtles and frogs is well documented. It is called intersex change and is characterised by the finding of female eggs in male testes. 1 These are not hermaphrodites but were true males. The scientists involved in the study of this emerging phenomenon attribute this change to environmental pollutants. Among the culprits since the inception of global industrialization, steroidal estrogens have become an emerging and serious concern. Worldwide, steroid estrogens including estrone, estradiol and estriol, pose serious threats to soil, plants, water resources and humans. Indeed, estrogens have gained notable attention in recent years, due to their rapidly increasing concentrations in soil and water all over the world. Concern has been expressed regarding the entry of estrogens into the human food chain which in turn relates to how plants take up and metabolise estrogens. 2 As an indication to the scale of the problem 70 to 100% of small mouth bass sampled from 19 sites in the US had intersex change!

Fertility level is one manifestation of hormonal health and another is sex appropriate behaviour. It is not unreasonable to suggest that the "new man" is not just a cultural animal secondary to societal trends. He may also have a touch of the intersex phenomenon suffered by his fishy friends and be unable to maintain a gentlemanly masculinity in keeping with the times - because he just hasn't got the hormones! Cultural swing in the past 50 years is widely acknowledged to be toward feminization. 3 Environmental pollutants and in particular agents that block hormonal action are beginning to take their toll. Such phenomena have not been reported in the non-Western World. Are stellar sportsmen and male Olympic medallists over represented south of the equator? Just a suggestion...?

1. Lindsey Konkel. National Geographic. Feb 3; 2016.
2. Environmental impact of estrogens on human, animal and plant life: A critical review.
MuhammadAdeelaXiaomingSongaYuanyuanWangaDennisFrancisaYuesuoYangab. https://doi.org/10.1016/j.envint.2016.12.010
3. Denis Prager. National Review. Nov 3; 2015.

Competing interests: No competing interests

12 October 2017
eugene G breen
psychiatrist
Mater Misericordiae University Hospital Dublin.
Mater Hospital Dublin

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