Comment

www.thelancet.com/oncology Vol 14 May 2013 443

obesity.7 Furthermore, much of the swelling that occurs with arm lymphoedema is fat not fl uid, which has led to liposuction as a treatment for breast cancer-related lymphoedema when fi rst-line decongestive lymphatic therapy (manual lymph drainage, compression and exercises) has fully resolved the fl uid component.8

The lymphatic system is the most common route for cancer spread and, in theory, blocking that route would do much to reduce cancer mortality. The problem has been that for centuries the lymphatic system has been the subject of gross neglect, mainly because of the absence of investigations to realise its importance to human pathology and disease. But that shortfall is changing, with the discovery of new lymphatic genes and molecular proteins.7 However, until a new drug that can modulate lymph fl ow or lymphatic function is developed, the lymphatic system, and in particular lymphoedema, will remain under-recognised by most practising oncologists. Attempts at improving lymph drainage by surgical means has had a resurgence with the development of lymphaticovenular anastomoses9 and lymph-node transfer operations.10 Lymph-node transfer combined with VEGF-C to stimulate lymphangiogenesis is entering phase 1 trials.7 Ideally, such developments will generate greater awareness and interest in lymphoedema, which

remains one of the most common and distressing consequences of breast cancer and its treatment.

Peter Mortimer St George’s Hospital Medical School, University of London, London SW17 0RE, UK; and The Royal Marsden Hospital, London SW3 6JJ, UK mortimer@sgul.ac.uk

I declare that I have no confl icts of interest.

1 Disipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol 2013; published online March 27. http://dx.doi.org/10.1016/S1470-2045(13)70076-7.

2 Browse N. Aetiology and classifi cations of lymphoedema. In: Browse N, Burnand KG, Mortimer PS, eds. Diseases of the lymphatics, London: Arnold, 2003. 151–57.

3 Stanton AW, Modi S, Bennett Britton TM, et al. Lymphatic drainage in the muscle and subcutis of the arm after breast cancer treatment. Breast Cancer Res Treat 2009; 117: 549–57.

4 Jensen MR, Simonsen L, Karlsmark T, Bülow J. Microvascular fi ltration is increased in the forearms of patients with breast cancer-related lymphedema. J Appl Physiol 2013; 114: 19–27.

5 Modi S, Stanton AW, Svensson WE, Peters AM, Mortimer PS, Levick JR. Human lymphatic pumping measured in healthy and lymphoedematous arms by lymphatic congestion lymphoscintigraphy. J Physiol 2007; 583: 271–85.

6 Stanton AW, Modi S, Mellor RH, Levick JR, Mortimer PS. Recent advances in breast cancer-related lymphoedema of the arm: lymphatic pump failure and predisposing factors. Lymphat Res Biol 2009; 7: 29–45.

7 Alitalo K. The lymphatic vasculature in disease. Nat Med 2011; 17: 1371–80.8 Damstra RJ, Voesten HG, Klinkert P, Brorson H. Circumferential suction

assisted lipectomy for lymphoedema after surgery for breast cancer. Br J Surg 2009; 96: 859–64.

9 Suami H, Chang DW. Overview of surgical treatments for breast cancer related lymphoedema. Plast Reconstr Surg 2010; 126: 1853–63.

10 Lähteenvuo M, Honkonen K, Tervala T, et al. Growth factor therapy and autologous lymph node transfer in lymphoedema. Circulation 2011; 123: 613–20.

Published OnlineApril 9, 2013http://dx.doi.org/10.1016/S1470-2045(13)70121-9

See Articles page 516

ACT II: treatment of anal cancer comes full circleIn 1974, Nigro and colleagues1 reported the results of treatment of three patients with anal cancer with preoperative pelvic radiation therapy (30 Gy in 15 fractions) with one cycle of fl uorouracil (25 mg/kg per 24 h) infused continuously over 5 days and bolus mitomycin (0·5 mg/kg) infused on day 1, then abdominoperineal resection roughly 6 weeks later. Two patients had no residual cancer in the resection specimen and the third patient had a complete clinical response, declined surgery, and was doing well without recurrence 13 months later. For a cancer that had been historically managed by extirpative surgery often with unsatisfactory outcomes and devastating sequelae, these fi ndings pointed to a potential breakthrough in treatment, aiming for cure, sphincter preservation, and enhanced quality of life.

Since Nigro’s report, clinical trials2 have established radiation therapy with concurrent fl uorouracil and mitomycin as the defi nitive treatment of anal cancer,

with surgery reserved for salvage. These studies have also reported poor results for patients with locally advanced tumours and signifi cant rates of acute and late treatment-related toxic eff ects. Many advances have also been made in our understanding of the biology of this disease and the crucial role of human papillomavirus in its development. These fi ndings have led to innovative screening and prevention strategies for patients at high risk of developing anal cancer.3

Randomised trials from Europe4,5 and the USA6–9 have explored changes to the standard template of radiation treatment with concurrent fl uorouracil and mitomycin to improve outcomes in patients with locally advanced anal cancer and reduce treatment-related toxic eff ects. Modifi cations have included induction or maintenance chemotherapy, radiation dose escalation, and planned treatment interruptions or substitution of mitomycin with cisplatin.

Comment

444 www.thelancet.com/oncology Vol 14 May 2013

In the Lancet Oncology, Roger James and colleagues4 report the results of a randomised 2×2 factorial trial of radiation therapy and chemotherapy with or without maintenance chemotherapy for squamous-cell carcinoma of the anus. The trial is the largest phase 3 trial for anal cancer. 940 patients with T1–T4 squamous-cell carcinoma of the anal canal and anal verge were randomly assigned to receive mitomycin (12 mg/m2 on day 1; n=472) or cisplatin (60 mg/m2 on days 1 and 29; n=468) with fl uorouracil (1000 mg/m2 on days 1–4 and 29–32) and radiation therapy (50·4 Gy in 28 daily fractions). They were also randomly assigned to either two courses of maintenance chemotherapy (fl uorouracil and cisplatin 5 and 8 weeks after chemoradiation; n=448) or no maintenance (n=446). This trial design provided suffi cient statistical power to address two comparisons: a direct comparison of mitomycin versus cisplatin in patients receiving chemoradiation, with the endpoints of complete response at 26 weeks and acute toxic eff ects; and the value of maintenance chemotherapy versus no maintenance as assessed by 3-year progression-free survival. Median follow-up was 5·1 years.

Complete response at 26 weeks after chemoradiation was 90·5% (391 of 432 patients) in the mitomycin group versus 89·6% (386 of 431 patients) in the cisplatin group (diff erence –0·9%, 95% CI –4·9 to 3·1; p=0·64). The proportion of patients who had acute toxic eff ects (grade 3 or 4) was similar in each group: 71% (334/472) versus 72%

(337/468). Non-haematological grade 3 or 4 toxic eff ects occurred in 294 of 472 (62%) patients versus 316 of 468 (68%) patients and any haematological grade 3 or 4 toxic eff ects occurred in 124 of 472 (26%) patients versus 73 of 468 (16%). 3-year progression-free survival was 74% in the maintenance group and 73% in the no maintenance group (hazard ratio 0·95, 95% CI 0·75–1·21; p=0·70). The investigators concluded that chemoradiation with fl uorouracil and cisplatin had similar complete response and overall toxic eff ects as fl uorouracil and mitomycin, but less haematological toxic eff ects. Maintenance chemotherapy did not improve progression-free survival. Thus, they advocate fl uorouracil plus mitomycin and 50·4 Gy in 28 fractions as standard practice and ascribe their outcomes to an effi cient radiobiological schedule.

Two other contemporary trials have investigated treatment of anal cancer—RTOG 98-11 and the ACCORD 3 trial (table).5–9 In RTOG 98-11, 682 patients were randomly assigned to receive treatment with induction fl uorouracil and cisplatin, followed by concurrent fl uorouracil and cisplatin with radiation therapy versus concurrent fl uorouracil and mitomycin and radiation therapy without induction.6–9 In the ACCORD 3 trial,5 all treatment groups (induction and initial combined modality treatment) received cisplatin, not mitomycin chemotherapy. Patients were assigned to receive a total radiation dose of either 60 Gy or 65–70 Gy after a 3 week rest period following combined modality treatment. A 2×2 factorial design provided suffi cient statistical power to address two

Primary site

N Stage Treatments Colostomy-free survival (%)*

Overall survival (%)*

Grade 3 or 4 haematological toxic eff ects (%; n/N)

Grade 3 or 4 non-haematological toxic eff ects (%; n/N)

Late toxic eff ects (%; n/N)

RTOG 98-116–9

Anal canal

682 T2 to T4, N0 to N3

Group A: EBRT (45–59 Gy) + fl uorouracil and mitomycinGroup B: fl uorouracil and cisplatin → EBRT (45–59 Gy) + fl uorouracil and cisplatin

Group A: 71·9%Group B: 65·0%

Group A: 78·3%Group B: 70·7%

Group A: 61% (199/324)Group B: 42% (134/320)

Group A: 74% (240 /324)Group B: 74% (239/320)

Grade 4 small or large bowel: 1% (6/625)

ACCORD 35 Anal canal

307 ≥4cm, <4cm, N1 to N3

Group A: fl uorouracil and cisplatin → EBRT (45 Gy) + fl uorouracil and cisplatin → rest→ 15 GyGroup B: fl uorouracil and cisplatin → EBRT (45 Gy) + fl uorouracil and cisplatin → rest → 20–25 Gy Group C: EBRT (45 Gy) + fl uorouracil and cisplatin → rest → 15 Gy Group D: EBRT (45 Gy) + fl uorouracil and cisplatin → rest → 20–25 Gy

Group A: 69·6%Group B: 82·4%Group C: 77·1%Group D: 72·7%

Group A + group B: 75%Group C + group D: 71%Group A + group C: 71%Group B + group D: 74%

Group A + group B: 19% (29/150)Group C + group D: 12% (19/157)

Group A + group B diarrhoea: 9% (14/150)Group C + group D diarrhoea: 12% (18/157)

Grade 4 colostomy: 3% (9/307)

ACT II4 Anal canal or anal margin

940 T1 to T4, N– or N+

Group A: EBRT (50·4 Gy) + fl uorouracil and cisplatinGroup B: EBRT (50·4 Gy) + fl uorouracil and mitomycinGroup C: EBRT (50·4 Gy) + fl uorouracil and cisplatin → fl uorouracil and cisplatinGroup D: EBRT (50·4 Gy) + fl uorouracil and mitomycin → fl uorouracil and cisplatin

Group A: 72%Group B: 75%Group C: 75%Group D: 73%

Group A: 84%Group B: 86%Group C: 83%Group D: 82%

Mitomycin: 26% (124/472)Cisplatin: 16% (73/468)

Mitomycin: 62% (294/472)Cisplatin: 68% (316/468)

Colostomy: 2% (14/844)

EBRT=external beam radiation therapy. *At 5 years in RTOG 98-11 and ACCORD 3, at 3 years in ACT II.

Table: Phase 3 randomised trials of anal cancer

Comment

www.thelancet.com/oncology Vol 14 May 2013 445

questions (the role of induction cisplatin and fl uorouracil, and total radiation dose) but not the individual results of the four treatment groups.

The data in these three trials can be summarised by the endpoints of colostomy-free survival, overall survival, and grade 3 or 4 acute and late toxic eff ects.4–9 First, the results of these three studies show that additional chemotherapy provides no benefi t to colostomy-free survival or overall survival (as induction or maintenance).

Second, the results of ACT II show that cisplatin compared with mitomycin does not improve of complete response rates or overall toxic eff ects with radiation therapy and fl uorouracil. Likewise, 3-year colostomy-free survival and overall survival did not diff er signifi cantly between cisplatin and mitomycin groups. The long-term results9 of RTOG 98-11 show that disease-free and overall survival was signifi cantly lower for patients receiving induction and concurrent cisplatin compared with concurrent mitomycin.

Third, acute toxic eff ects are common in treatment of anal cancer, with haematological grade 3 or 4 toxic eff ects in up to 61% of patients and non-haematological grade 3 or 4 toxic eff ects in up to 74% of patients, irrespective of treatment approach. Finally, little progress has been made in improving the outcomes of patients with advanced primary tumours.4,5,7 In the ACT II trial,4 patients with tumours larger than 5 cm had unacceptably high failure rates, with 3 year progression-free survival of 62–67% versus 80–84% for patients with tumours 5 cm or smaller.

Ultimately, the results of these trials do not suggest a groundbreaking improvement in outcome for these patients, especially those with very advanced local disease. At present, radiation therapy with fl uorouracil and mitomycin remains the standard of care. Acute toxic eff ects can be mitigated by innovations in radiation

delivery—eg, intensity-modulated radiation therapy techniques—which are being rapidly adopted into clinical practice.10 Clinical trials are underway to assess EGFR inhib i tors with radiation therapy and chemotherapy. Further understanding of the biology of human papillo-mavirus in anal cancer and translation of this knowledge to screening, prevention, and treatment resistance are also needed to advance the care of these patients.

*Christopher G Willett, Brian G Czito, Manisha PaltaDepartment of Radiation Oncology, Duke University, Durham, NC 27710, USAchristopher.willett@duke.edu

We declare that we have no confl icts of interest.

1 Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–56.

2 Flam M, John M, Pajak T, et al. Role of mitomycin in combination with fl uorouracil and radiotherapy, and of salvage chemoradiation in the defi nitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized Intergroup study. J Clin Oncol 1996; 14: 2527–39.

3 Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365: 1576–85.

4 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, open-label, 2×2 factorial trial. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/S1470-2045(13)70086-X.

5 Peiff ert D, Tournier-Rangeard L, Gerard JP, et al. Induction chemotherapy and dose intensifi cation of the radiation boost in locally advanced anal canal carcinoma: fi nal analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 2012; 30: 1941–48.

6 Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs. fl uorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized trial. JAMA 2008; 299: 1914–21.

7 Ajani JA, Winter KA, Gunderson LL, et al. US Intergroup anal carcinoma trial: tumor diameter predicts for colostomy. J Clin Oncol 2009; 27: 1116–21.

8 Ajani JA, Winter KA, Gunderson LL, et al. Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the Intergroup trial (RTOG 98-11). Cancer 2010; 116: 4007–13.

9 Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fl uorouracil/mitomycin versus fl uorouracil/cisplatin. J Clin Oncol 2012; 30: 4344–51.

10 Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fl uorouracil and mitomycin-C for reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2012; published online Nov 12. DOI:10.1016/j.ijrobp.2012.09.023.

CHOP intensifi cation: not yet state of the artAddition of the anti-CD20 agent rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and pre d -ni sone) chemotherapy represents the most impor tant progress in the treatment of diff use large B-cell lymphoma in the past 30 years. Rituximab in combination with CHOP-like chemotherapy (R-CHOP) is now the worldwide accepted standard for all patients with diff use large B-cell lymphoma.1–3 Interval reduction between CHOP

cycles from 3 weeks (CHOP21) to 2 weeks (CHOP14) improved outco mes signifi cantly for elderly patients with diff use large B-cell lymphoma;4 however, these elderly patients did not receive rituximab. In The Lancet Oncology, Richard Delarue and colleagues report the LNH03-6B study,5 a randomised comparison of eight cycles of R-CHOP every 3 weeks (R-CHOP21) or 2 weeks (R-CHOP14) in 602 elderly patients with diff use large B-cell lymphoma.

Published OnlineApril 9, 2013http://dx.doi.org/10.1016/S1470-2045(13)70156-6

See Articles page 525