NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of radiation therapy for early Dupuytren s disease In Dupuytren s disease, connective tissue in the hands (called the palmar fascia) becomes thickened and shortened (contracted). This causes ridges in the palm, and stiff fingers that bend towards the palm and cannot be straightened The aim of treatment is to soften the contracted tissue to allow the patient to regain use of their hand. Radiation therapy for early Dupuytren s disease involves directing low energy X-rays at the affected tissue with the aim of restoring hand function and/or preventing progression. Treatment can be repeated in some patients. Introduction The National Institute for Health and Clinical Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in January Procedure name Radiation therapy for early Dupuytren s disease Specialty societies British Association of Plastic, Reconstructive and Aesthetic Surgeons British Orthopaedic Association British Society for Surgery of the Hand Royal College of Radiologists IP overview: radiation therapy for early Dupuytren s disease Page 1 of 17

2 Description Indications and current treatment Dupuytren s disease is a benign, slowly progressive condition of unknown origin. The disease is characterised by a thickening of the connective tissue in the palm of the hand, which form nodules and cords, leading to difficulty in extending the fingers. Symptoms may include pain and reduced hand function in terms of range of motion. Most people with Dupuytren s disease are affected in both hands. The most commonly involved digit is the ring finger, followed by the little finger and then the middle finger. Treatment seeks to restore hand function and/or prevent progression. There are a number of non-surgical treatments for Dupuytren s disease, such as vitamin E cream applied as topical therapy and ultrasonic therapy. A less invasive surgical intervention is needle fasciotomy in which fibrous bands (contractures) in the connective tissue are divided using the bevel of a needle. Open surgical correction may be a treatment option in later-stage disease when secondary changes to tendons and joints have developed. What the procedure involves The perceived benefit of this procedure is to help avoid (or postpone) the need for surgical intervention; however, the underlying disease will usually remain and contracted finger joints will rarely regain their movement. The mechanism of action of radiation therapy is unclear. Treatment is thought to affect the development of cells (fibroblasts) within the palmar fascia and reduce their growth rate. In radiation therapy the nodules and cords associated with Dupuytren s disease are usually irradiated from a distance of a few centimetres, either with superficial X-rays that do not penetrate deeply into the body, or with electrons (electron beam therapy). Treatment is typically performed on several consecutive days, until the planned radiation dose (usually about 15 Gy in 5 fractions) has been delivered. Depending on how severe the condition is, more than 1 course of treatment, separated by a few weeks, particularly if there is disease of the proximal interphalangeal joint is sometimes used. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to radiation therapy for Dupuytren s disease. Searches were conducted of the following databases, covering the period from their commencement to 9 December 2009 and updated to 23 July 2010: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published IP overview: radiation therapy for early Dupuytren s disease Page 2 of 17

3 studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Criteria Publication type Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patient Patients with early Dupuytren s disease Intervention/test radiation therapy (X-rays, gamma rays, electron beam) Outcome Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Language Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the overview This overview is based on approximately 250 patients from 1 randomised controlled trial 1,2 and 2 case series 3,4. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. IP overview: radiation therapy for early Dupuytren s disease Page 3 of 17

4 Table 2 Summary of key efficacy and safety findings on radiation therapy for early Dupuytren s disease Abbreviations used: Study details Key efficacy findings Key safety findings Comments Seegenschmiedt M H (2001) 1 Number of patients analysed: 129 (63 group A, 66 group Complications Follow-up issues: B) Randomised controlled trial Germany Recruitment period: 1997 to 1998 Study population: patients with clinically evident and progressive early stage Dupuytren s disease. 53% bilateral treatment required. Previous treatment prior to radiation therapy included local excision/partial fasciotomy (19%), topical steroid injections (5%), systemic nonsteroidal anti-inflammatory drugs, local vitamin E (19%), other drugs (12%), other therapeutic measures (9%). 34% burning / itching / pressure or tension. Mean lag from onset of symptoms to radiation therapy treatment 26 months. n = 129 (63 group A; 66 group B; 2 different dose regimens), 198 hands. Age: 62 years (mean). Sex: 52% male Patient selection criteria: not reported. Technique: radiation therapy applied at a distance of 40 cm with areas of the palm not involved shielded by lead rubber plates. Group A: 10 fractions of 3 Gy (total dose 30 Gy) in 2 periods of treatment separated by 8 weeks. Group B: 7 fractions of 3 Gy (total 21 Gy) on alternate days. Dupuytren s disease stage Subjective symptom assessment at 12 months. By patients treated. Group A Group B Regression of 65.1% (41/63) 53.0% (35/66) symptoms Stable condition 30.2% (19/63) 40.9% (27/66) Progression 7.9% (5/63) 12.1% (8/66) Measurement of significance between groups not reported. Objective symptom assessment (number and consistency of cords, nodules, and extension deficit) at 12 months. By hands treated. Group A Group B Regressed 55.8% (53/95) 53.4% (55/103) Stable 36.8% (35/95) 37.9% (39/103) Progression 7.4% (7/95) 8.7% (9/103) No statistically significant differences were found between the groups. Overall across the 2 groups treatment failure (new nodules) was reported in 5.5% (11/198) of hands, (new cords) in 3.5% (7/198), and (increased flexion deformity) in 6.1 % (12/198). Total number of nodules Group A Group B Baseline months months p < 0.01 for both groups compared with baseline No statistically significant differences were found between Follow-up: 1 year minimum. the groups. Conflict of interest/source of funding: not IP overview: radiation therapy for early Dupuytren s disease Page 4 of 17 Corrective hand surgery was required in 3% (4/129) patients within 1 year of follow-up. Overall acute (to 4-week follow up) toxicity events: Outcome Rate (198 hands) Skin dryness/redness 38.4% (76/198) Extensive erythema 6.1% (12/198) Dry desquamation 5.1% (10/198) Wet desquamation 1.5% (3/198) Pronounced swelling 1.5% (3/198) There was no statistically significant difference in the rate of acute toxic complications between group A (35.8% [34/95]) and group B (52.4% [54/103]). Overall chronic toxicity events: Group A Group B 3 months 15.8% (15/95) 10.7% (11/103) 12 months 4.2% (4/95) 4.9% (5/103) Most of these events were dryness, increased desquamation, mild skin atrophy, or slight subcutaneous fibrosis requiring ointments. Alteration of heat and pain sensation occurred in 4.0% (8/198) of hands. 3 patients in group A refused the second week of treatment. Analysed on intention-to-treat principle. Study design issues: Authors state significant subjective and objective reduction of symptoms, nodules, and cords in both treatment groups (p < 0.01), however this may relate to changes from baseline for both groups, rather than difference between groups. Safety outcomes are reported overall and not by group. Methods of randomisation and blinding not reported. Study population issues: Patient demographics and clinical status (number of nodules, cords and stage) not significantly different between the groups at baseline. Other issues: Method of evaluation of efficacy outcomes not clear. Dupuytren s disease stage evaluated at baseline but not explicitly

5 Abbreviations used: Study details Key efficacy findings Key safety findings Comments reported Total number of cords Seegenschmiedt M H (2001) cont. Group A Group B Baseline months months p < 0.01 for both groups compared with baseline No statistically significant differences were found between the groups. reported at follow-up assessment. Authors state that prophylactic radiation therapy should not impair good surgical results. IP overview: radiation therapy for early Dupuytren s disease Page 5 of 17

6 Abbreviations used: Study details Key efficacy findings Key safety findings Comments Pohl S (2002) 2 Presented abstract: efficacy outcomes not extracted. Complications Follow-up issues: Randomised controlled trial There was no statistically significant difference in the rate of acute skin changes between group A (12.8% [10/78]) and group B (17.8% [16/90]). 3 patients in group A refused the second week of treatment. Germany Recruitment period: 1997 onwards Study population: Patients with early stage Dupuytren s disease. n = 110 (168 hands; 78 group A, 90 group B). Age: 56 years (mean). Sex: 56% male Patient selection criteria: not reported Technique: radiation therapy applied at a distance of 40 cm with areas of the palm not involved shielded by lead rubber plates. Group A: 10 fractions of 3 Gy (total dose 30 Gy) in 2 periods of treatment separated by 8 weeks. Group B: 7 fractions of 3 Gy (total 21 Gy) on alternate days. There was no statistically significant difference in the rate of chronic minor side effects (skin dryness, or change in heat and pain sensation) between group A (14.1% [11/78]) or group B (15.6% [14/90]). Period of follow-up not reported. Study design issues: Methods of randomisation and blinding not reported. Study population issues: Patient demographics and most clinical factors (number of nodules, and stage) not significantly different between the groups at baseline. However there were more cords present in group A. Other issues: probably the same patients as included in Seegenschmiedt (2001). Follow-up: 3 years minimum Conflict of interest/source of funding: not reported. IP overview: radiation therapy for early Dupuytren s disease Page 6 of 17

7 Abbreviations used: Study details Key efficacy findings Key safety findings Comments Betz N (2010) 3 Number of patients analysed: 96 (142 hands) Complications Case series Germany Recruitment period: 1982 to 2006 Study population: patients with early stage Dupuytren s disease. Bilateral 85%. 23% of patients had a lag from diagnosis to radiation therapy >48 months. n = 135 (208 hands) Age: Not reported. Sex: not reported Patient selection criteria: not reported Technique: radiation therapy applied at a distance of 40 cm with areas of the palm not involved shielded by lead rubber plates. Two course of 5 fractions of 3 Gy (total dose 30 Gy) in 2 periods of treatment separated by 6 weeks. Follow-up: 13 years (median) Dupuytren s disease stage Clinical assessment at medan 13 years follow-up: Disease regression 9.6% (20/208) Stable disease 59.1% (123/208)) Progression 31.3% (65/208) Patients with progressive disease treated within 1 year of diagnosis showed significantly better long-term results than those treated after 48 months Symptoms at median 13years follow-up (n = 87) Progression 19.5% (17/87) Complete relief 16.1% (14/87) Good relief 18.4% (16/87) Minor relief 32.2% (28/87) Unchanged 13.8% (12/87) 20.2% (42/208) of hands required subsequent surgery). Treatment toxicity was evaluated using the European Organisation Research and Treatment of Cancer criteria. Outcomes reported within the treated area only. Long-term outcome All minor long-term 31.7% (66/208) changes Dry skin and increased 22.6% (47/208)) desquamation Mild skin atrophy with 6.7% (14/208) occasional telangiectasia Erythema at up to 1 year 2.4% (5/208) Most patients complained of itching and burning during treatment. No chronic grade 3 or 4 reactions were observed. There was no induction of cancer at final follow up. Follow-up issues: Retrospective study, complete follow-up available for 76% (135/178) hands treated. 31 patients had died, 12 lost to follow-up, Study design issues: Treatment aim was prevention of disease progression. Method for assessment of subjective efficacy outcomes not described. It is not clear whether clinical assessment of functional status was based on the stage score that was measured at baseline. 4 hands had worse symptoms while Dupuytren s disease stage remained unchanged. Study population issues: Excluded patients had a similar clinical and demographic characteristics to those analysed. Conflict of interest/source of funding: not reported. Other issues: 6.7% (9/135) patients had received previous treatment either surgery or local steroids. IP overview: radiation therapy for early Dupuytren s disease Page 7 of 17

8 Abbreviations used: Study details Key efficacy findings Key safety findings Comments Finney R (1953) 4 Number of patients analysed: 25. Complications Follow-up issues: Case series UK Recruitment period: not reported Study population: patients with Dupuytren s disease without secondary changes to tendons or joints. n = 25 Dupuytren s disease stage Baseline score assessed using a 6-stage criteria: Stage 1 (nodules in palmar fascia but no contracture or nodules in skin but not palmar fascia) n = 3 Stage 2 (nodules in the palmar fascia involving the skin but no flexion deformity) n = 4 Stage 3 (nodules in the palm invading the skin plus flexion contracture in 1 or more finger) n = 18 Subjective improvement including softening of nodules, lessening of paraesthesia, and increase in finger movement within the first 4 weeks. Some skin dryness and occasional slight erythema (absolute numbers not reported). Method of follow-up not reported (presumed retrospective). Time points of follow-up assessment not described. Loss to follow-up not reported. Study design issues: Method of delivery of radiation was different for patients with grade 3 Dupuytren s disease. Age: not reported Sex: not reported Patient selection criteria: not reported Technique: gamma radiation at 1 to 1.5 cm; 8 fractional doses for 8 days, total dose 3000 roentgens. Follow-up: 2 to 10 years (range) Conflict of interest/source of funding: not reported. Objective improvement with increased movement began at a mean of 1.7 months, and greatest improvement gained at 6.0 months. Full functional recovery 32.0% (8/25) Functional improvement 28.0% (7/25) (not normal function) Limited improvement 16.0% (4/25) Unchanged 12.0% (3/25) All patients in whom full recovery was observed were stage 1 or 2 at baseline. At final follow-up (2 to 10 years) 75% of patients were improved and 25% remained static. Study population issues: Patient baseline demographics not reported. Other issues: Intervention used may not be identical to modern radiation therapy delivery techniques. However it is broadly similar and the only published data available from a UK setting. IP overview: radiation therapy for early Dupuytren s disease Page 8 of 17

9 Efficacy A randomised controlled trial of 129 patients (198 hands) reported that objective symptom assessment (number and consistency of cords and nodules, and degree of extension deficit) showed regression of Dupuytren s disease in 56% (53/95) of hands treated with 30 Gy of radiation and in 53% (55/103) of hands treated with 21 Gy at 1-year follow-up (no significant difference between groups) 1. The same trial reported that subjective symptom assessment (not otherwise defined) showed regression of Dupuytren s disease was achieved in 65% (41/63) of patients in a group treated with 30 Gy of radiation therapy, and 53% (35/66) of patients treated with 21 Gy at 1-year follow-up 1 (level of significance between groups not stated). A case series of 135 patients (208 hands) reported that complete relief of symptoms was achieved in 16% (14/87) of patients; there was a good relief in symptoms in 18% (16/87), a minor relief in 32% (28/87), symptoms were unchanged in 14% (12/87) and symptoms had progressed in 20% (17/87) at median 13 years follow-up 3. The same case series reported improved clinical status in 10% (20/208) of hands at a median of 13 years follow-up. Disease was stable in 59% (123/208) of hands and progression was reported in 31% (65/208) of hands 3. A case series of 25 patients reported full functional recovery in 32% (8/25) of patients, with maximum benefit achieved at 6.0 months. At final follow-up (range 2 to 10 years) 75% of patients had improved (not otherwise defined) 4. Safety The randomised controlled trial of 129 patients (198 hands) reported that chronic toxicity events occurred in 16% (15/95) of hands treated with 30 Gy of radiation and 11% (11/103) of hands treated with 21 Gy at 3-month follow-up 1 (level of significance not stated). Most of these events were skin dryness, increased desquamation, mild skin atrophy, or slight subcutaneous fibrosis requiring ointments. Across both study groups alteration of temperature and pain sensation occurred in 4% (8/198) of hands (minimum follow-up 1 year). In a subset of 110 patients (168 hands) from the same study there was no significant difference in the rate of acute skin changes between patients treated with 30 Gy of radiation (13% [10/78]) or 21 Gy of radiation (18% [16/90]) 2. The case series of 135 patients (208 hands) reported mild skin atrophy with occasional telangiectasia in 7% (14/208) of hands, and minor skin dryness and increased desquamation in 23% (47/208) of hands at 13-year follow-up 3. The case series of 25 patients reported some skin dryness and occasional slight erythema (absolute numbers not reported) at 2 to 10-year follow-up 4. IP overview: radiation therapy for early Dupuytren s disease Page 9 of 17

10 Validity and generalisability of the studies Radiation technique, dose and fractionation vary between studies. There is little systematic evaluation of safety outcomes such as long-term complications relating to irradiation. Different classifications for assessing Dupuytren s disease have been used in the studies included. Efficacy outcomes are largely subjective. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Needle fasciotomy for Dupuytren's contracture. NICE interventional procedure guidance 43 (2004). Available from Specialist Advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society. Mr C Bainbridge (British Society for Surgery of the Hand), Mr V Deveraj (British Society for Surgery of the Hand), Mr G Giddens (British Society for Surgery of the Hand), Mr J Glees (Royal College of Radiologists), Miss M Spittle (Royal College of Radiologists). Two Specialist Advisers classified the procedure as novel and of uncertain safety and efficacy (in the UK), and 2 classified it as established and no longer new. There is no comparator to this procedure, in later stages of Dupuytren s contracture surgical correction is used. IP overview: radiation therapy for early Dupuytren s disease Page 10 of 17

11 Theoretical adverse events may include skin dryness, recurrence, scarring / hand stiffness, and long-term potential for developing radiation induced cancer. One Specialist Adviser stated that theoretical adverse events were those of any low-dose irradiation procedure. The main efficacy outcomes for this procedure should include prevention of recurrence and the onset of contracture, restoration of hand function, patient satisfaction, and rate of recurrence/requirement of surgery. The precise dose of radiation to be applied is currently uncertain, and one adviser noted that it is not always effective. In the UK, nodules are not commonly operated on as there may be a lack of symptoms and there is uncertainty as to whether or not they will ever progress onto cords (and cause the fingers to flex). Uncertainties regarding the efficacy of the procedure include patient selection (stage / size of nodule to treat), problems relating to later surgery, and influence of comorbidities or concomitant drugs. Patient Commentators opinions NICE s Patient and Public Involvement Programme sent 23 questionnaires to 1 trust for distribution to patients who had the procedure (or their carers). NICE received 20 completed questionnaires. The Patient Commentators raised the following issues about the safety/efficacy of the procedure which did not feature in the published evidence or the opinions of Specialist Advisers, and which the Committee considered to be particularly relevant: One patient reported that they had to protect their hand from the sun (photosensitivity). IP overview: radiation therapy for early Dupuytren s disease Page 11 of 17

12 Issues for consideration by IPAC Non-English-language studies were not included in this overview because it was considered that sufficient data in English were available. However, a considerable number of studies in other languages (particularly German) have been published. This procedure has not been widely used in the UK; however the notification of this procedure to NICE indicated that there is at least 1 centre wishing to provide it. IP overview: radiation therapy for early Dupuytren s disease Page 12 of 17

13 References 1 Seegenschmiedt MH, Olschewski T, Guntrum F. (2001) Radiotherapy optimization in early-stage Dupuytren's contracture: first results of a randomized clinical study. International Journal of Radiation Oncology, Biology, Physics 49: Pohl S, Hinke A, Attassi M et al. (2002) Prophylactic radiotherapy in Dupuytren's contracture: three years outcome. International Journal of Radiation Oncology Biology Physics 54: Betz N, Ott O J, Adamietz B et al. (2010) Radiotherapy in early-stage Dupuytren's contracture: Long-term results after 13 years. Strahlentherapie und Onkologie 186: Finney R. (1953) Dupuytren's Contracture. A radiotherapeutic approach. The Lancet 2: IP overview: radiation therapy for early Dupuytren s disease Page 13 of 17

14 Appendix A: Additional papers on radiation therapy for early Dupuytren s disease There were no additional papers identified. IP overview: radiation therapy for early Dupuytren s disease Page 14 of 17

15 Appendix B: Related NICE guidance for radiation therapy for early Dupuytren s disease Guidance Interventional procedures Recommendations Needle fasciotomy for Dupuytren's contracture NICE interventional procedures guidance 43 (2004) 1.1 Current evidence on the safety and efficacy of needle fasciotomy for Dupuytren s contracture appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. IP overview: radiation therapy for early Dupuytren s disease Page 15 of 17

16 Appendix C: Literature search for radiation therapy for early Dupuytren s disease Database Date searched Version/files Cochrane Database of 09/12/09 Issue 4, 2009 Systematic Reviews CDSR (Cochrane Library) Database of Abstracts of 09/12/09 N/A Reviews of Effects DARE (CRD website) HTA database (CRD website) 09/12/09 N/A Cochrane Central Database of 09/12/09 Issue 4, 2009 Controlled Trials CENTRAL (Cochrane Library) MEDLINE (Ovid) 09/12/ to November Week MEDLINE In-Process (Ovid) 09/12/09 December 08, 2009 EMBASE (Ovid) 09/12/ to 2009 Week 49 CINAHL (NLH Search 09/12/ to Present 2.0/EBSCOhost) BLIC (Dialog DataStar) 30/11/ to date The following search strategy was used to identify papers in MEDLINE. A similar strategy was used to identify papers in other databases. 1 Radiation Dosage/ 2 (Radi* adj3 (Therap* or Dos* or Treat*)).tw. 3 Radiotherapy/ 4 Radiotherap*.tw. 5 Radiation, Ionizing/ 6 ((Ionizin* or Ionisin*) adj3 Radi*).tw. 7 X-Rays/ 8 (X ray* adj3 (therap* or treat*)).tw. 9 X radiation*.tw. 10 or/ Fibroma/ 12 Fibroblasts/ 13 Fascia/ IP overview: radiation therapy for early Dupuytren s disease Page 16 of 17

17 14 or/ Hand/ 16 (Hand* or Palm* or Finger*).tw. 17 or/ and Dupuytren's Contracture/ ((Dupuytren* or Palmar*) adj3 (Contracture* or Disease* or Morbus*)).tw. ((Hand* or Palm* or Finger*) adj3 (Fibro* or Myxofibro* or Fascia*)).tw. (Flexion* adj3 Deformit* adj3 (Hand* or Palm* or Finger*)).tw. 23 or/ and Animals/ not Humans/ not 25 IP overview: radiation therapy for early Dupuytren s disease Page 17 of 17