Не знаю, что делать..

[Vrag]

Этот же товарищ опубликовал [editorial] в том же журнале четыре года назад. Тоже очень эмоциональная статья. Я ее сюда скопирую. [It reviews the late effects of radiotherapy on breast cancer risk, based on existing evidence (the previous editorial that I pasted was focused on cerebrovascular events)]

[Vrag]

[Logo DL. Radiation Therapy in Hodgkin Disease: Why Risk a Pyrrhic Victory? J Natl Cancer Inst Volume 97, Number 19 Pp. 1394-1395, October 5, 2005

Correspondence to: Dan L. Longo, MD, National Institute on Aging, 5600 Nathan Shock Dr., Box 9, Baltimore, MD 21224-6825 (e-mail: [email protected]).

Pyrrhus became King of Epirus in Northern Greece in 306 BC. He was a brilliant warrior and strategist; for example, he employed elephants in his attack force 60 years before Hannibal's famous use of these animals in the Second Punic War. In 280 BC, he invaded Italy and won a great battle at Heraclea but suffered enormous losses of men in his army. A few months later, in 279 BC, he won a second major battle at Asculum, again enduring severe and irreplaceable casualties. After being complimented on his success by one of his men, he is said to have responded, "Another such victory and we are undone." Thus, through the centuries the term "Pyrrhic victory" has been used to mean a conquest won at too great a cost for the victor.

In this issue of the Journal, Travis et al. (1) have studied the largest number of cases of secondary breast cancer after treatment for Hodgkin disease (106 patients) published to date. Most epidemiologic studies provide relative risks but never translate the results into an absolute risk that can be shared in a way the patient understands. However, Travis et al. have done a case–control study and computed cumulative absolute risks for developing breast cancer as a function of dose of radiation therapy and use of alkylating agent–based chemotherapy. The results are shocking. For a 25-year-old woman who received typical mantle-field radiation therapy for her Hodgkin disease, the risk of developing breast cancer by age 55 years is 29% (95% confidence interval [CI] = 20.2% to 40.1%). For a 25-year-old woman receiving a lower dose of radiation (20–40 Gy), the risk of developing breast cancer by age 55 years is 24.6% (95% CI = 16.6% to 24.8%). In addition, no evidence suggests that the risk declines after 30 years. According to Surveillance, Epidemiology, and End Results (SEER) data, a 25-year-old woman in the general population has about a 3% risk of developing breast cancer by age 55 years.

Absolute risks are much easier to put in proper perspective than relative risks. Recall that millions of women stopped taking hormone replacement therapy that was controlling their menopausal symptoms and preserving their bone mineral density because of an increased relative risk of breast cancer that translates into quite a modest cumulative absolute risk (2). A 50-year-old woman has one chance in 16 of developing breast cancer over the next 30 years (6.25%). A 50-year-old woman who takes hormone replacement therapy for 10 years has one chance in 13 of developing breast cancer over the next 30 years (7.7%). The absolute risk is increased 1.5% in 30 years; yet women and physicians have largely abandoned hormone replacement therapy. Unlike Hodgkin disease, menopausal symptoms are not life-threatening; however, the point is that some medical practices change dramatically as a consequence of only small changes in absolute risk.

We have been slow to recognize the many costs to the patient of using radiation therapy to treat Hodgkin disease; or, if not slow to recognize the costs, then slow to change our choice of therapy because of the costs. Most of the 7350 people diagnosed with Hodgkin disease in 2005 will be treated with combined modality therapy. The rationale for this physician behavior appears to be the hope (for there is precious little evidence) that lowering the dose of radiation therapy to 24 Gy or so will dramatically lower the risk of the major side effects, including second cancers and accelerated coronary artery disease.

Most evidence suggests that lower doses of exposure to radiation produce a lower risk of developing second cancers, but the risk never reaches zero. In the dose range for therapeutic radiation in Hodgkin disease, the dose–risk curve is not deeply sloped. The article by Travis et al. does not suggest that the risk falls very much in the range of 20–40 Gy (see their table 2). Most therapeutic radiation for Hodgkin disease used as a supplement to chemotherapy is given in the dose range of 20–24 Gy. Breast cancer incidence increases as a consequence of therapeutic radiation administered at low doses for benign diseases and even from repeated diagnostic radiography [for review, see the work of Boice (3)]. Factors affecting risk are complicated and include age, age at exposure, dose, energy of the radiation, duration of exposure, condition being treated, and overall risk of breast cancer in the individual and in the population exposed (4). In women who receive breast irradiation as part of their treatment for primary breast cancer, the nonirradiated breast receives an average radiation dose of 2.82 Gy (5). Such women younger than 45 years at time of treatment experience a 60% increase in second cancers in the incidentally irradiated contralateral breast. Even the internal radiation that makes it to the breast during radiation therapy for cervical cancer can increase the risk of breast cancer. In one series (6), the relative risk of breast cancer was 3.1 (95% CI = 0.5 to 20.0) for exposures of 0.5 Gy or greater in women without ovaries with cervical cancer (the absence of which would be expected to reduce the risk). No increased risk was noted in the group whose breasts received 0.24 Gy or less. As pointed out in the June 2005 report of the 7th Biological Effects of Ionizing Radiation (BEIR) Committee, done under the auspices of the National Academy of Sciences, there is no safe dose of radiation. Resistance to this notion must play a role in the continued use of radiation therapy in Hodgkin disease treatment, especially its use in the face of an effective alternative, combination chemotherapy alone.

Travis et al. suggest that their projections do not apply in patients treated with "modern approaches" involving limited-field radiation therapy. That suggestion seems weak at best. The last person treated in their cohort had been disease free for 1 year on December 31, 1994, 11 years ago. Has someone invented a method of delivering mantle-field radiation therapy that is novel in the last decade? Does any new method permit radiating axillary nodes without irradiating the breast? Can one deliver radiation to the mediastinum without it passing through the overlying skin and skin appendages? Has any new method been proven effective in curing the disease or in improving the efficacy of chemotherapy? Has this novel, effective modification of the mantle field been used in patients monitored for 20 years or more and been shown to reduce the risk of second cancers and premature coronary artery disease? Would these not normally be the minimal requirements for routinely using an intervention that had been shown to produce breast cancer in up to 30% of the women in whom it was used?

What is most perplexing about the persistent practice of using radiation therapy routinely in the treatment of Hodgkin disease is the availability of alternative approaches (combination chemotherapy alone) that are just as successful in curing the disease and are not associated with such a magnitude of late fatal complications. The literature is quite clear that combined radiation therapy and chemotherapy does not produce a superior overall survival to chemotherapy alone in any stage of disease (7–9). Why accept any increased risk of breast cancer from a treatment that is not required?

Travis et al. provided us with an important, quantitative way to speak to our patients with Hodgkin disease about the risk of developing breast cancer after radiation therapy. We need similar information about all the other kinds of radiation-induced cancers and about the radiation-accelerated coronary artery disease that affects patients cured of Hodgkin disease with therapy that includes radiation. Indeed, we need similar information about long-term risks for all interventions for all the diseases we treat. Given the facts about the enormous risk of breast cancer after mantle-field radiation therapy, we now need to act on them.

[Vrag]

продолжение [For the patients who have already been exposed to radiation therapy and remain at risk, we need to counsel them and provide heightened surveillance. We should look at the risk of male breast cancer in men who were treated with mantle-field radiation therapy for Hodgkin disease. We know very little about how radiation-induced breast cancer relates to sporadic breast cancer biologically. What percentage of patients has estrogen and progesterone receptor–positive disease? Does the pattern of gene expression resemble sporadic localized breast cancer or metastatic breast cancer? Although there is much that remains unknown, we have some tools to combat this problem. From the lower incidence of secondary radiation-induced breast cancers in women without ovaries, women whose ovaries have been irradiated, and women with alkylating agent–induced menopause, we can infer that many (perhaps half) of these radiation-induced breast cancers might be prevented by 5 years of tamoxifen therapy. In addition, women who received mantle-field radiation therapy should be included with other women at increased risk in clinical trials evaluating newer chemoprevention strategies (e.g., aromatase inhibitors). Given that the level of risk in some subsets of women (e.g., women treated with 20–40 Gy at age 25 or 30 years have a 25%–34% risk of developing breast cancer in 30 years) are as high as some women with hereditary breast cancer, consideration needs to be given to prophylactic mastectomy for those at greatest risk. Finally, we need to stop exposing women to the risk of subsequent breast cancer (and other malignancies and heart disease) by needlessly using radiation therapy as a component of their Hodgkin disease treatment. A Pyrrhic victory in the absence of reasonable alternative ways to accomplish the goal can be tragic but necessary; a Pyrrhic victory that could be avoided while still accomplishing the goal is just foolish.

REFERENCES

(1) Travis LB, Hill D, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst 2005;97:1428–37.[Abstract/Free Full Text]
(2) Coombs NJ, Taylor R, Wilcken N, Boyages J. Hormone replacement therapy and breast cancer: estimate of risk. Br Med J 2005;331:347–9.[Free Full Text]
(3) Boice JD Jr. Radiation and breast carcinogenesis. Med Pediatr Oncol 2001;36:508–13.[CrossRef][Web of Science][Medline]
(4) Preston DL, Mattsson A, Holmberg E, Shore R, Hildreth NG, Boice JD Jr. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts. Radiat Res 2002;158:220–35.[CrossRef][Web of Science][Medline]
(5) Boice JD Jr, Harvey FB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 1992;326:781–5.[Abstract]
(6) Boice JD Jr, Blettner M, Kleinerman RA, Engholm G, Stovall M, Lisco H, et al. Radiation dose and breast cancer risk in patients treated for cancer of the cervix. Int J Cancer 1989;44:7–16.[Web of Science][Medline]
(7) Loeffler M, Brosteanu O, Hasenclever D, Sextro M, Assouline D, Bartolucci AA, et al. Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 1998;16:818–29.[Abstract]
[8] Specht L, Gray RG, Clarke MJ, Peto R. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group. J Clin Oncol 1998;16:830–43.[Abstract]
(9) Straus DJ, Portlock CS, Qin J, Myers J, Zelenetz AD, Moskowitz C, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 2004;104:3483–9.[Abstract/Free Full Text]]

[Vrag]

Все это личное мнение одного товарища (высказанное в очень эмоциональной форме), но тут надо учитывать два фактора: (1) [this oppinion is based on published evidence] и (2) [these editorials were published in the Journal of the National Cancer Institute - a peer-reviewed publication with a very high impact factor]. Чепуху там не публикуют как правило.

(я также лично знаю некоторых авторов тех статей на чьи работы он ссылается, хотя непосредственно с ними не работал)

[Vrag]

[The purpose of my posts up to this point was to demonstrate that

(1) The issue is controvercial and different experts have different oppinions on this matter (contrary to what Malyshka have asserted) and

(2) The late effects of radiotherapy may be substantial and seem to occur with high probability

We must now consider the potential benefits from the use of radiotherapy] в звизюшином случае.

[I will review the existing evidence directly (without relying on editorials), since it is more limited]

[Vrag]

The study which is most relevant to our case was conducted at Memorial Sloan-Kettering Cancer Center (New York) and published in 2004. Full citation is given below

Straus DJ, et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood. 2004 Dec 1;104(12):3483-9. Epub 2004 Aug 17.


In this trial, patients were randomized either to 6 cycles of ABVD alone or 6 cycles of ABVD followed by RT. Eligibility criteria were as follows:

Stages IA, IB, IIA, IIB, or IIIA and lack of bulky disease (mediastinal mass ratio < 0.33, no adenopathy > 10 cm)

A total of 76 patients were randomized to ABVD-plus-radiotherapy and 76 were randomized to ABVD alone.

65 patients in each group (65 / 76 = 86%) achieved complete remission. There were 15 patients who relapsed from complete remission during the median follow-up time of 67 months: 7 in the ABVD-plus-radiotherapy group and 8 in the ABVD-alone group.

So the proportions of patients who relapsed after complete remission were 7/65 = 11% with radiotherapy and 8/65 = 12% without radiotherapy.

There were 33 patients who had discontinuation of bleomycin due to pulmonary toxicity. Discontinuation of bleomycin did not obviously affect the outcome.

There was insufficient follow-up time to assess long term toxicities in this study.

[Vrag]

This study showed that addition of radiotherapy to ABVD

[1] does not completely prevent disease recurrence after complete remission (7 of 65 patients in the ABVD-plus-radiotherapy arm experienced disease recurrence after initial complete remission)

[2] radiotherapy does not seem to have a large impact on the probability of disease recurrence

Although this study was based on relatively small numbers of patients, it essentially ruled out a very large benefit from radiation in terms of disease recurrence. So if radiation has any effect, it is probably relatively small in magnitude.

[Malishka]

[I want to emphasize that the use of radiation therapy in Hodgkin’s disease following complete response to chemotherapy (particularly for stage I-II) is a controversial issue. The NCCN panel favors its use, particularly for bulky disease (as defined in my post 3347, this definition of bulky disease is based on the definition used in clinical trials and in the NCCN guidelines). However, chemotherapy alone is recognized as a reasonable alternative by the panel. This is shown in the treatment algorithm on page 7 of the pdf file of the NCCN guidelines. This issue is also addressed in the discussion section of guidelines.]

[Yesterday, Inquisitor expressed the opinion of one of his colleagues, who apparently would not favor the use of radiotherapy in zvizdyusha’s case. There are other experts in this field who would agree with this recommendation. I will paste here an editorial published very recently in the Journal of the National Cancer Institute] (статья опубликована 2 недели назад)

Vrat, listen very carefully: we are all expressing JUST an opinion here, some more educated and some not. It's all good, BUT!!! Zvizda has a primaray oncologist and already a radiation oncologist who gave HIS opinion and his opinion was to suggest radiation! Thus, she is going for a SECODN opinion with someonw who will see ALL her records (not just some) and who will EXAMINE her in person and have a discussion. Not you, not me, not Inkvizitor's friend

Guidelines are good. Uptodate gets updated every 6 months and incorporates NCCN guidelines as well as quotes the text (or do u think the studies used for Uptodate are different from NCCN???!) There are areas of controversy and there always will be, especially with Hodgkin's where survival is up to 90%.

Zvizda will see a 2nd opinion and will make a decision :34:

[Malishka]

Все это личное мнение одного товарища (высказанное в очень эмоциональной форме), но тут надо учитывать два фактора: (1) [this oppinion is based on published evidence] и (2) [these editorials were published in the Journal of the National Cancer Institute - a peer-reviewed publication with a very high impact factor]. Чепуху там не публикуют как правило.

(я также лично знаю некоторых авторов тех статей на чьи работы он ссылается, хотя непосредственно с ними не работал)

Vrag, these are EDITORIALS!
Study reviews in general just like studies themselves should be devoid of emotion; there is no place for subjective feelings

[Vrag]

[I will describe here two more trials of ABVD and radiotherapy.

The first trial was conducted by the National Cancer Institute of Canada and the Eastern Cooperative Oncology Group (USA). The full citation is given below

Meyer RM, et al. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42.

I will only describe the part of the trial which is relevant to our case.

A total of 276 patients with stage I-II unfavorable disease (but no bulky disease) were randomized to ABVD with radiotherapy (139 patients) or ABVD alone (137 patients). At five years of follow-up, freedom from disease progression was 95% in the radiotherapy group and 88% in the ABVD-alone group.

This information is less applicable to our case because the initial complete response proportions were not reported and so I cannot calculate failure from progression among patients who achieved complete response initially. Also, not all patients in this trial completed 6 cycles. Some completed 4 (if they had no detectible disease after 2 cycles). And the radiotherapy was more aggressive than what is currently recommended. Nevertheless, these results suggest that addition of radiotherapy may reduce the risk of recurrence among the patients with unfavorable stage I-II disease. But the magnitude of this protective effect does not seem to be very large.]