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JOURNAL OF CLINICAL ONCOLOGY

End Points in Anal Cancer: Hopes for a Common Language TO THE EDITOR: The International Rare Cancers Initiative (IRCI) has developed a trial for metastatic/relapsed anal cancer. Further international studies will be undertaken. The International Conference on Harmonisation (ICH) guidelines1 and the CONSORT statement2 recommend that time-to-event end points should be precisely defined. Six phase III randomized controlled trials in squamous cell cancers of the anus3-9 demonstrate variably defined primary/secondary end points leading to a lack of comparability, and their validity to provide recommendations for optimal treatment can be questioned. In the future we need agreed consistent definitions. Cancer-Related and Time-to-Event End Points Locoregional failure and colostomy-free survival (CFS) are the most relevant end points for anal cancer, but not all studies reported them. Overall survival is a clear end point, but competing risks in this elderly population and subsequent salvage treatment may alter the observed treatment effect. We recommend future trials report overall and causespecific survival, as well as deaths due to causes other than anal cancer. Table 1 shows the variation in the time to events included in each trial. At randomization all patients have measurable disease. After chemoradiotherapy the majority is disease-free, but up to 10% will have persistent disease. This does not fit end points such as disease-free survival (DFS; usually used following surgery when there is no detectable tumor) and progression-free survival (where all patients have disease at baseline). In Anal Cancer Trial (ACT) I the primary end point was defined as local control3—a composite of locoregional failure and requirement for a colostomy. For contemporary trials separate data on disease and colostomy status is required. We would suggest an adapted definition of DFS with noncomplete response (timed 11-18 weeks after chemoradiotherapy), ra-

C O R R E S P O N D E N C E

diological local, nodal, pelvic, or distant disease recurrence after chemoradiotherapy complete response or death from any cause counted as an event—analyses should use date of registration/ randomization as the date of origin. CFS is measured from treatment initiation to colostomy, death, or lastfollow-upevaluationifpatientwasstillalivewithnosurgery.Although CFS captures both inability to control the primary tumor and the need to ameliorate late effects, CFS itself is a poorly discriminating end point, because of potential interventions (initial colostomy for symptoms and the rate of surgical salvage will vary between units). Pretreatment colostomy is not fundamentally part of the randomized allocation. Yet the literature freely compares CFS between trial arms in the same way as DFS. Response has been assessed by clinical response and radiological imaging at varying time-points and needs to be sustained for 4 weeks. The optimum timing is 6 months, and there is a balance between waiting for a response versus need for early salvage surgery before the tumor becomes unresectable.10 Patients who never attain local control (after chemoradiotherapy) are considered as treatment failures at randomization. Compliance and Adverse Effects Reports tend to focus on acute toxicity for the assessment of safety analysis, but this information is not necessarily helpful clinically or to aid future patient decision making. Acute toxicity and compliance assessments can be subjective, and are sometimes measured using different assessment tools. Varying time frames following completion of treatment are used. Defining death events as treatment related is subjective. It may be better to report cause of death as anal cancer, treatment related, or as noncancer deaths. Simple statements on compliance rates are unhelpful. For cancers treated with primary chemoradiotherapy full compliance to radiation is more important than minor dose reductions of chemotherapy. Median doses received/overall duration of treatment time with interquartile ranges are required. Compliance is high with the

Table 1. End Points Used in Anal Cancer Trials End point Disease-related time to event end points Local recurrence Local recurrence, distant metastases, new tumor ⫹ death Local recurrence, distant metastases, ⫹ death Local recurrence, new tumor ⫹ death Local recurrence, distant metastases, colostomy rate ⫹ death Local recurrence ⫹ colostomy due to recurrence/complications Survival end points All deaths Anal cancer and treatment-related deaths Colostomy-related time to event end points Colostomy any cause or death

ACT 13,9

EORTC4

RTOG 87045

RTOG 98116

DFS

DFS

ACCORD 037

ACT II8

LRF PFS EFS EFS LRF OS CSS CFS

OS CSS CIS

CFS

CR (CFS)

Abbreviations: ACT, Anal Cancer Trial; CFS, colostomy-free survival10; CIS, cumulative incidence of colostomy; CR, colostomy rate; CSS, cause-specific survival; DFS, disease-free survival; EFS, event-free survival; EORTC, European Organisation for Research and Treatment of Cancer; LRF, locoregional failure; OS, overall survival; PFS, progression-free survival (PFS reported although recurrence-free survival in protocol); RTOG, Radiation Therapy Oncology Group.

Journal of Clinical Oncology, Vol 32, No 12 (April 20 ), 2014: pp 1281-1284

© 2014 by American Society of Clinical Oncology

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Correspondence

first chemotherapy, but poorer for subsequent courses. Causes of noncompliance are usually toxicity related, or based on patients’ preferences, which is rarely documented. Late effects were not specifically reported in any trial. The current Radiation Therapy Oncology Group late effects instrument11 is not sufficiently specific. Long-term quality of life (QoL) was not reported in phase III trials, due to the absence of robust contemporary instruments. Patients are poor at reporting symptoms12 and while questionnaires can increase responses, they aren’t designed to identify radiotherapy-associated as opposed to premorbid conditions. We require novel instruments. Given the potential effect of pelvic radiotherapy on QoL,13 we recommend using patient-reported outcomes in future trials. In conclusion, we require consensus on unambiguous end point definitions.14 End points should be relevant to clinicians and patients and we recommend DFS as primary end point with other end points reported to provide data in this rare disease: response at 18 to 26 weeks, CFS, cancer-specific survival, overall survival, acute toxicity including treatment-related deaths, late toxicity, and QoL. We hope this letter will prompt an international consensus statement, ensuring a broad and objective input from recognized experts.

Rob Glynne-Jones Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom

Richard A. Adams Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom

Mark Jitlal and Helen Meadows Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Rob Glynne-Jones, Roche (C), Nocletron (C), Sanofi (C), Eli Lilley (C), Merck Serono (C) Stock Ownership: None Honoraria: Rob Glynne-Jones, Roche, Merck Serono, Sanofi, Pfizer Research Funding: Rob Glynne-Jones, Merck Serono, Roche, Sanofi Expert

Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Food and Drug Administration: International Conference on Harmonization: Guidance on Statistical Principles for Clinical Trials—Availability: FDA—Notice. Fed Regist 63:49583-49598, 1998 2. Schulz KF, Altman DG, Moher D: CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152: 726-732, 2010 3. UKCCCR Anal Cancer Working Party: Epidermoid Anal Cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin. Lancet 348:1049-1054, 1996 4. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997 5. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized Intergroup study. J Clin Oncol 14:2527-2539, 1996 6. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin and radiotherapy vs fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal: A randomised controlled trial. JAMA 199:1914-1921, 2008 7. Peiffert D, Tournier-Rangeard L, Ge´rard JP, et al: Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: Final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 30:1941-1948, 2012 8. James RD, Glynne-Jones R, Meadows HM, et al: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): A randomised, phase 3, openlabel, 2⫻2 factorial trial. Lancet Oncol 14:516-524, 2013 9. Northover J, Glynne-Jones R, Sebag-Montefiore D, et al: Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 102:1123-1128, 2010 10. Glynne-Jones R, James R, Meadows H, et al: Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II. J Clin Oncol 30:240s (suppl; abstr 4004), 2012 11. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 12. Andreyev HJN, Davidson SE, Gillespie C, et al: Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut 61:179-192, 2012 13. Bentzen AG, Balteskard L, Wanderås EH, et al: Impaired health-related quality of life after chemoradiotherapy for anal cancer: Late effects in a national cohort of 128 survivors. Acta Oncol 52:736-744, 2013 14. Bellera CA, Pulido M, Gourgou S, et al: Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: Formal consensus method for the development of guidelines for standardised time-to-event endpoints’ definitions in cancer clinical trials. Eur J Cancer 49:769-781, 2013

DOI: 10.1200/JCO.2014.55.1515; published online ahead of print at www.jco.org on March 17, 2014 ■ ■ ■

Survival Benefit From ResponseGuided Approach: A Direct Effect of More Effective Cytotoxic Regimens or an Indirect Effect of ChemotherapyInduced Amenorrhea? TO THE EDITOR: Minckwitz et al1 recently reported results from the GeparTrio trial. In their article, the authors reported a significantly 1282

© 2014 by American Society of Clinical Oncology

higherdisease-freeaswellasoverallsurvivalforresponse-guidedchemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC ⫻ 8 or TAC ⫻ 2 plus vinorelbine and capecitabine [NX] ⫻ 4) than for conventional chemotherapy (TAC ⫻ 6). More interestingly, the survival benefit from response-guided chemotherapy was observed in hormone receptor–positive tumors (luminal like) but not in hormone receptor–negative tumors (human epidermal growth factor receptor 2 positive and triple negative). The authors concluded that response-guided neoadjuvant chemotherapy might improve survival and is more effective in hormone receptor–positive tumors. However, we have concerns related to the cause of the survival benefit from the JOURNAL OF CLINICAL ONCOLOGY

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End points in anal cancer: hopes for a common language.

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