Become an NLN member, enjoy exclusive benefits!
| Join Our Mailing List |
If you need the Adobe reader for pdf documents, download it here:
We have recently updated/revised our website and we would appreciate your
feedback so that we can continue to make improvements to better serve you by
providing an efficient and user-friendly website.
Financial Assistance for Compression Garments
8th NLN Conference, August 27-31, 2008, San Diego CA
Groundbreaking Medicare Decision:
Compression Garments are Prosthetic Devices!
New Book: 4th ed, Lymphedema: Diagnosis and Therapy, H. Weissleder
For Professionals: NLN Research Survey
Updated NLN Online Patient Questionnaire
NLN Position Papers: Risk Reduction, Treatment, Exercise, Air Travel, Training
Seeking Patients: Breast Cancer Survivor Studies
Volume 20, No. 1 January ~ March 2008
Volume 20, No. 2 April ~ June 2008
Volume 20, No. 3 July ~ September 2008
Gynecologic malignancies account for 11.5% of cancers diagnosed in women. 1 In the year 2007, it is estimated that 76,150 women will be newly diagnosed with ovarian, uterine, cervical, or vulvar cancer. 2 Surgery is the primary treatment for most patients with gynecologic malignancies, which often includes lymph node dissections and, in select cases, postoperative radiation therapy. As a result of such aggressive oncologic treatment, such patients are at significant life-long risk for lower-extremity lymphedema. It has been noted that prior to surgical treatment, gynecologic cancer patients are often not informed about the potential for developing lymphedema. Because the primary focus is on the treatment and management of the malignancy, the risks and physical impact of postoperative morbidities, including lymphedema, are often not addressed. 3
Although much has been written about post-breast cancer treatment upper-extremity lymphedema, data about lower-extremity lymphedema in the gynecologic cancer population is sparse. The objective of this report is to: 1) summarize contemporary data pertaining to the incidence, risk factors, presentation, diagnostic strategies, and treatment of the most common gynecologic malignancies and, 2) to review the published literature related to the prospective assessment of lymphedema following the treatment of gynecologic malignancies.
Ovarian Cancer
Ovarian cancer is the most common gynecologic malignancy and occurs in 1 in 70 women, with an estimated 22,430 new cases in 2007. 4 It is also among the most lethal gynecologic malignancies, accounting for over 15,000 deaths per year. The median age at diagnosis is 61 years. Approximately 10% of ovarian cancer cases are hereditary, and most of these are associated with a hereditary breast/ovarian cancer syndrome (BRCA-1 and BRCA-2 gene mutations) or hereditary nonpolyposis colorectal cancer (HNPCC, or Lynch syndrome), which is characterized by the development of multiple cancers, including endometrial, colorectal, and ovarian cancers. Risk factors for nonhereditary or sporadic ovarian cancer include increased age, nulliparity (women who have never been pregnant), early menarche (onset of menstrual periods before age 12), late menopause, delayed childbearing, and Ashkenazi Jewish heritage. 2
The diagnosis of ovarian cancer is often delayed owing to the lack of specific signs and symptoms associated with the disease. Two thirds of patients with ovarian cancer are found to have advanced disease at presentation, with tumor implantation in the peritoneal cavity or outside of the pelvis with metastasis to the retroperitoneal or inguinal lymph nodes (stage III disease) or with distant metastatic disease (stage IV). For patients who present with suspected ovarian cancer, evaluation includes physical examination, cancer antigen (CA)-125 measurement, a complete blood count (CBC), liver function tests, comprehensive metabolic panel, and radiologic imaging, consisting of chest radiography and pelvic ultrasonography or abdominopelvic computed tomography (CT).
Ovarian cancer treatment includes surgical staging and cytoreduction (debulking), and, in most instances, postoperative systemic chemotherapy with platinum- and taxane-based chemotherapy. Surgical staging includes a thorough intra-abdominal exploration and a total abdominal hysterectomy, bilateral salpingo-oophorectomy (removal of the ovaries), omentectomy, and selective pelvic and para-aortic lymph node sampling. At the time of surgical exploration, every attempt should be made to achieve maximal tumor debulking, or removal of all visible tumor or to the point that the largest residual tumor implant measures less than 1 cm. 5
Uterine Cancer
Uterine cancer accounts for 39,080 new malignancies annually in the United States. 6 The most common type of uterine cancer develops in the endometrium. The median age at diagnosis is 63 years. As with ovarian cancer, up to 10% of endometrial cancer cases are hereditary and associated with HNPCC. Risk factors for nonhereditary or sporadic endometrial cancer include nulliparity, early menarche, late menopause, obesity, unopposed estrogen therapy, and chronic diseases such as diabetes and hypertension. 2 Most patients with endometrial cancer present with complaints of abnormal uterine bleeding or postmenopausal bleeding. The evaluation of such patients includes a physical examination, CBC and platelet count, endometrial biopsy to obtain pathologic confirmation of the disease, and chest radiography. If extrauterine disease is suspected, additional evaluation should include CA-125 testing and abdominopelvic magnetic resonance imaging (MRI) or CT. Endometrial cancer metastasizes primarily by tumor invasion into adjacent anatomic structures, including the cervix, vagina, or adnexa. Metastasis to distant sites by lymph node or bloodstream can also occur.
Surgery is the primary treatment for endometrial cancer and includes exploratory laparotomy, hysterectomy, bilateral salpingo-oophorectomy (removal of the fallopian tubes and ovaries), and dissection of the pelvic and para-aortic lymph nodes. 7 For patients with surgically resectable extrauterine disease, omentectomy and surgical debulking are performed. Pathologic information obtained from surgical staging guides postoperative treatment planning, which may include radiation treatment and/or chemotherapy. Radiation therapy can also be delivered as the primary therapy for selected patients. For patients with advanced or recurrent disease, the most common chemotherapy agents are platinum agents, doxorubicin, and taxanes. 2 For patients with extrauterine disease, inoperable disease, or recurrent disease, whole-pelvic radiation therapy or brachytherapy can be used.
Cervical Cancer
Cervical cancer is the most common cause of cancer-related death in women in underdeveloped countries. 6 In the United States, about 11,150 new cases of cervical cancer are diagnosed annually. Cervical cancer is a sexually transmitted disease that is associated with the human papillomaviruses. Risk factors for developing cervical cancer include sexual intercourse beginning at an early age, multiple sexual partners, multiparity, and a history of smoking. 2 Presenting symptoms often include vaginal discharge and abnormal bleeding. Physical examination, CBC and platelet count, and cervical biopsy are required for diagnosis. Preoperative staging includes chest radiography, CT of the chest, abdomen, and pelvis for patients with advanced disease, and optional cystoscopy and proctoscopy. Cervical cancer can metastasize by invading surrounding anatomic structures, lymphatic spread, hematogenous dissemination, and intraperitoneal implantation.
The treatment for patients with microinvasive disease (≤ 3 mm deep) includes a simple hysterectomy or cervical conization when fertility is an issue. For patients with cervical lesions that invade more than 3 mm deep, there is a significant risk of recurrence; therefore, radical hysterectomy and pelvic lymph node dissection with or without para-aortic lymph node sampling are performed. For patients with advanced disease, radiation therapy and concurrent cisplatin-based chemotherapy improve overall survival. 2
Vulvar Cancer
Vulvar cancer was diagnosed in 3,490 patients in 2007. 6 Risk factors for vulvar cancer include the human papilloma viruses, advanced age, low socioeconomic status, hypertension, diabetes, a history of lower genital tract malignancies, and immunosuppression. 2 The most common symptoms at presentation are itching, ulceration, and nodules in the region. For patients with suspected vulvar cancer, evaluation includes physical examination with punch biopsy of the suspected lesion, laboratory assessment, and chest radiography. Vulvar cancer can spread by local extension via the lymphatics or hematogenously to distant sites.
Treatment for vulvar cancer involves excision of the primary lesion or, if the primary lesion is greater than 2 cm in diameter, radical vulvectomy. Surgical staging often includes sentinel lymph node biopsy of the superficial inguinal nodal regions. Superficial inguinal lymph node dissections are recommended if the lesion is 2 cm or more from the midline, and both superficial and deep inguinal lymph node dissections are the standard treatment for lesions greater than 2 cm in diameter. Patients with metastatic disease undergo surgery plus preoperative or postoperative radiation therapy with or without radiation-sensitizing chemotherapy. 2
Lymphedema
Although the pathophysiology resulting in the development of lymphedema following treatment of gynecologic malignancies is not completely defined, the combination of resection of pelvic lymph nodes together with the gravitational influences on lymphatic flow can result in congestion and lower extremity lymphedema. Figure 1 depicts the pelvic anatomy with the extensive lymphatic drainage patterns from the perineum to the inguino-femoral lymph nodes and from the pelvic organs to the lymph nodes of the iliac/obturator and para-aortic region.
To identify studies of lymphedema in cancer, we conducted a review of the literature in the PubMed database using the search terms “lymphedema” and “cancer,” which identified 2,182 articles. From these, we selected those articles pertaining to gynecologic malignancies and selected only those studies which had examined lymphedema prospectively. Only 21 prospective studies were identified that examined the incidence of lymphedema in patients following treatment for gynecologic malignancies 2, 4, 5, 8-26. These studies were published between 1978 and 2007 and included various numbers of patients (range: 3 to 402 patients). In total, 2,589 patients with gynecologic malignancies were evaluated with a median follow-up of 40 months. Most patients (88.1%) assessed had undergone a hysterectomy with a pelvic lymph node dissection followed by radiation therapy. The remaining patients (11.9%) were treated with vulvectomy. Overall, the incidence of lower extremity lymphedema varied from 0% to 42% in these reports, with an overall average incidence of lymphedema calculated as 22.5%. Given the significant limitations associated with the studies, this likely represents an underestimation of the true incidence of lymphedema. The most significant of these limitations is related to the lack of objective methods used to measure lower extremity lymphedema. Volume measurement using water displacement is regarded as the most sensitive and accurate measure of lymphedema; however, only one study 18 reported using this method. Two studies 2, 8, 9, 23, 27 utilized questionnaires, one study 13 used quantitative data from magnetic resonance imaging (MRI), and the remaining 18 studies reported on lymphedema using clinical definitions or did not report the methods used at all.
Conclusions
Lymphedema is a common long-term complication following the treatment of gynecologic malignancies, although the true incidence and impact are not well documented in the current body of published literature. Prospective, longitudinal studies with objective measures, long-term follow-up and validated instruments for examining functional outcomes and quality of life are essential in order to determine the true extent of the problem. When the answers to these questions are known, then strategies for lymphedema prevention and risk reduction can be evaluated in the context of clinical trials. For example, the use of compression garments and/or self-applied manual lymphatic drainage in the early postoperative period should be evaluated in the context of a randomized clinical trial to determine whether these are effective techniques in reducing long-term lymphedema.
Lymphedema is known to be a significant cancer survivorship issue with a profound effect on the quality of life. 7, 28, 29 With advances in surgical treatment and the availability of more effective systemic agents, the number of women surviving gynecologic malignancies will likely increase over time. As a result, there will be a growing number of women at risk for developing lower extremity lymphedema. The Nation’s Investment in Cancer Research from the U.S. Department of Health and Human Services reported in 2006 that a priority of the organization was to optimize health and quality of life after cancer which includes reducing the long-term side effects of cancer treatment and improve symptom management. Given the incidence and the impact of secondary lymphedema related to cancer treatment in the United States, NCI supported clinical trials in lymphedema prevention and treatment should be a priority and are the key for future progress in the field.
Kristi Salter, PA-C is a certified physician assistant in the Department of Surgical Oncology at the University of Texas M. D. Anderson Cancer Center, Houston, TX.
Dr. Cormier is an Associate Professor in the Departments of Surgical Oncology and Biostatistics and Applied Mathematics at the University of Texas M. D. Anderson Cancer Center. She is also the Chair of the Medical Advisory Committee for the NLN.
Glossary of Terms
Adnexa - adjoining anatomical structures (e.g., ovarian structures adjoining the uterus)
Brachytherapy - placement of radioactive material directly into or near a tumor
Conization - surgery to remove a cone-shaped piece of tissue from the cervix and cervical canal
Cytoreduction / debulking - reducing the size of a tumor by removing all visible tumor or as much tumor as possible
Nulliparity - women who have never been pregnant
Menarche - onset of menstrual periods
Retroperitioneal - area outside or behind the peritoneum (abdominal cavity that contains gastrointestinal organs)
Salpingo-oophorectomy - removal of the fallopian tubes and ovaries
Staging - determining the extent of cancer spread in the body based on tumor size, lymph node involvement, and spread from the original site
Systemic - affecting the entire body
REFERENCES
1. American Cancer Society. Cancer Facts and Figures 2007. Available at: http://www.cancer.org/docroot/STT/STT_0.asp. Accessed October 22, 2007.
2. Slomovitz BM, Soliman PT, Wolf JK. Gynecologic Cancers. In: Feig BW, Berger DH, Fuhrman GM, eds. The M. D. Anderson Surgical Oncology Handbook, Department of Surgical Oncology. (Fourth ed). Houston: Lippincott Williams & Wilkins; 2006:520-563.
3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Available at: http://nccn.org/professionals/physicians_gls/default.asp. Accessed October 22, 2007.
4. Zhang X, Sheng X, Niu J, et al. Sparing of saphenous vein during inguinal lymphadenectomy for vulval malignancies. Gynecol Oncol. 2007;105:722-726.
5. Salama JK, Mundt AJ, Roeske J, Mehta N. Preliminary outcome and toxicity report of extended-field, intensity-modulated radiation therapy for gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2006;65:1170-1176.
6. Estimated new cancer cases and deaths by sex for all sites, US, 2007. Available at: http://www.cancer.org/docroot/stt/stt_0.asp.
7. Lockwood-Rayermann S. Lymphedema in gynecologic cancer survivors: an area for exploration? Cancer Nurs. 2007;30:E11-18.
8. Bergmark K, Avall-Lundqvist E, Dickman PW, Henningsohn L, Steineck G. Patient-rating of distressful symptoms after treatment for early cervical cancer. Acta Obstet Gynecol Scand. 2002;81:443-450.
9. Bergmark K, Avall-Lundqvist E, Dickman PW, Henningsohn L, Steineck G. Lymphedema and bladder-emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer. 2006;16:1130-1139.
10. Bellati F, Angioli R, Manci N, et al. Single agent cisplatin chemotherapy in surgically resected vulvar cancer patients with multiple inguinal lymph node metastases. Gynecol Oncol. 2005;96:227-231.
11. Judson PL, Jonson AL, Paley PJ, et al. A prospective, randomized study analyzing sartorius transposition following inguinal-femoral lymphadenectomy. Gynecol Oncol. 2004;95:226-230.
12. Gaarenstroom KN, Kenter GG, Trimbos JB, et al. Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gynecol Cancer. 2003;13:522-527.
13. Fujiwara K, Kigawa J, Hasegawa K, et al. Effect of simple omentoplasty and omentopexy in the prevention of complications after pelvic lymphadenectomy. Int J Gynecol Cancer. 2003;13:61-66.
14. Gould N, Kamelle S, Tillmanns T, et al. Predictors of complications after inguinal lymphadenectomy. Gynecol Oncol. 2001;82:329-332.
15. Uno T, Ito H, Itami J, et al. Postoperative radiation therapy for stage IB-IIB carcinoma of the cervix with poor prognostic factors. Anticancer Res. 2000;20:2235-2239.
16. Kridelka FJ, Berg DO, Neuman M, et al. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection. A pilot study. Cancer. 1999;86:2059-2065.
17. Logmans A, Kruyt RH, de Bruin HG, Cox PH, Pillay M, Trimbos JB. Lymphedema and lymphocysts following lymphadenectomy may be prevented by omentoplasty: A pilot study. Gynecol Oncol. 1999;75:323-327.
18. Snijders-Keilholz A, Hellebrekers BW, Zwinderman AH, van de Vijver MJ, Trimbos JB. Adjuvant radiotherapy following radical hysterectomy for patients with early-stage cervical carcinoma (1984-1996). Radiother Oncol. 1999;51:161-167.
19. Yeh SA, Wan Leung S, Wang CJ, Chen HC. Postoperative radiotherapy in early stage carcinoma of the uterine cervix: treatment results and prognostic factors. Gynecol Oncol. 1999;72:10-15.
20. Chatani M, Nose T, Masaki N, Inoue T. Adjuvant radiotherapy after radical hysterectomy of the cervical cancer. Prognostic factors and complications. Strahlenther Onkol. 1998;174:504-509.
21. Sundfor K, Trope CG, Kjorstad KE. Radical radiotherapy versus brachytherapy plus surgery in carcinoma of the cervix 2A and 2B--long-term results from a randomized study 1968-1980. Acta Oncol. 1996;35 Suppl 8:99-107.
22. Werngren-Elgstrom M, Lidman D. Lymphoedema of the lower extremities after surgery and radiotherapy for cancer of the cervix. Scand J Plast Reconstr Surg Hand Surg. 1994;28:289-293.
23. Bosze P, Meszaros I, Palfalvi L, Ungar L. Perioperative complications of 116 radical hysterectomies and pelvic node dissections. Eur J Surg Oncol. 1993;19:605-608.
24. Orr JW, Jr., Holloway RW, Orr PF, Holimon JL. Surgical staging of uterine cancer: an analysis of perioperative morbidity. Gynecol Oncol. 1991;42:209-216.
25. Fiorica JV, Roberts WS, Greenberg H, Hoffman MS, LaPolla JP, Cavanagh D. Morbidity and survival patterns in patients after radical hysterectomy and postoperative adjuvant pelvic radiotherapy. Gynecol Oncol. 1990;36:343-347.
26. Martimbeau PW, Kjorstad KE, Kolstad P. Stage IB carcinoma of the cervix, the Norwegian Radium Hospital, 1968-1970: results of treatment and major complications. I. Lymphedema. Am J Obstet Gynecol. 1978;131:389-394.
27. Clinical Practice Guidelines in Oncology - v.1.2007. National Comprehensive Cancer Network, Inc. Available at: www.nccn.org.
28. Appollo K. Lower-extremity lymphedema in a patient with gynecologic cancer. Oncol Nurs Forum. 2007;34:937-940.
29. Ryan M, Stainton MC, Jaconelli C, Watts S, MacKenzie P, Mansberg T. The experience of lower limb lymphedema for women after treatment for gynecologic cancer. Oncol Nurs Forum. 2003;30:417-423.
By Professor Neil B. Piller
Summary
A patient presents with no real cause for their lymphoedema; we call it “primary”. We superficially examine the patient, see if there are any clinically manifest external signs of lymph vascular malformation, ask them about the nature of their swollen limb, when it started, how it progressed, if there is a family history, make some measurements and if they are lucky, they may be able to be referred to a genetic specialist. In the examination, we may find (or be told of) other associated angio-dysplasias or associated syndromes such as distachiasis, webbed neck, or others. We classify and then begin treatment of the outwardly appearing symptoms of a dysfunctional lymphatic system. In reality, we have little idea of what has happened or is happening at the genetic, molecular and biochemical levels. We often cannot be sure of whether what we suggest will work. There is little or no pro-activity in this. We react and then treat in a “shotgun” approach with little knowledge or ability to target the real issues – that is the structure and functional aberrations of the lympho-vascular system. The time is right for change. Our better understanding of genetics and of molecular biology, specifically molecular lymphology will soon hopefully mean a change to this. We will be able to act on sound knowledge to change and improve the structure and/or function of the lymphatic system.
We are not there yet, but in the meantime the best we can do is early detection, recognition, and acknowledgement of a dysfunctional lymphatic system, hopefully leading to some prophylactic intervention (for those who have been lucky enough to gain an early referral) and an offering of the best treatment targeting the range of problems using a multidisciplinary team.
Article
Our genes are the blueprint for the body’s development, growth and functioning. However, sometimes there is an error in the code we get from each of our parents, sometimes the code is read wrongly, and sometimes the code changes as we move through life. These changes can affect our biochemical and physiological events which can lead to the manifestation of lymphoedema.
In the world of lymphoedemas and associated syndromes, these code and misreading errors are what can form the basis of a range of dysplasias of the lympho-vascular systems, the end point of which, for some, is the development of one of a range of what we currently call primary lymphoedemas. Lately it seems that the proportion of primary lymphoedemas compared to secondary ones seems to be declining. Perhaps this is a consequence of our ability now to more accurately determine the causes and paths of lymphoedemas than previously. Not withstanding this, when a primary lymphoedema (and its associated co-morbidities) manifest it is a situation which needs to be reacted to. It is important, to look back at the family history of the disorder, examine family members with clinical, sub-clinical or latent forms of lymphatic dysfunction, and then glance into the future for potential offspring who may also be at risk.
Sometimes these genetic errors are severe and the embryo fails to thrive, while on other occasions the errors are small. Depending on the nature of these errors and on the impact of this misreading or wrong reading of coded information, there can be aberrations to the structure and thus function of the lympho-vascular system and associated structures. The more wide spread these are across the lympho-vascular structures of the body, the earlier they present.
An example, is those surviving embryos with the earliest congenital form of lymphoedema (hereditary/type 1/Nonne-Milroy). It seems to affect boys and girls equally, is more common in the legs, but certainly occurs in the genitalia, arms, trunk and face at times. Its incidence is about 1 in 6000 births; in real terms it’s a fairly common genetic disorder. In this form of lymphoedema, the fault seems to be on chromosome 5 and with the VEGFR-3 (also known as FLT-4) gene for a majority of families.
For the later types of primary lymphoedema (juvenile and later onset/Meige), it’s different in that mostly girls are affected and then usually in one limb (or more so in one limb than the other). While the exact genes here are not certain, many of those who have it do not express it (develop lymphoedema), but there is still the risk that it will be passed to their children.
Often the genetic coding or transcription error which leads to lymphoedema (or to an increased risk of it) are associated with other disorders (commonly also with a genetic basis). Under these conditions the term “syndromic lymphoedema” is sometimes used. Examples of when lymphoedema occurs with other syndromes include, yellow nail syndrome (adults), distichiasis (teenagers mostly), choleostasis, intestinal lymphangiectasia, hypoparathyroidism, Noonan’s syndrome, microcephaly and a range of other infrequent but often significant conditions. In the case of distichiasis, there is a haplo-insufficiency due to a mutation in one allele of the gene which encodes the FOXC2 transcription factor (Erickson, 2001). An excellent paper to read about the syndromic classification of heritable lymphoedema is by Northup et al (2003).
What is clear is that a dysplasia of the lymphatic system often is associated with a range of other malformations in other structures and systems of the body. The severity of these malformations will often determine the timing of their appearance. (Chaft et al 2003). One gets the impression that a really pure primary lymphoedema is rare given the strong association of lymphangiopathies with carriers of chromosomal aberrations, Because of this, if one comes across a person with just a lymphangiopathic aberration (no matter what the age), there should perhaps be an attempt to screen for symptoms of chromosomal aberrations as described above.
Individuals with lymphangiopathies want to know what has gone wrong, what the future for those with these conditions is, and what may be done in the future to prevent or remediate them. Our best chance seems to be linked to our expansion of our knowledge of factors affecting the growth and development of the lympho-vascular system to the extent that we can use it to suppress abnormal growth of the lymph vascular system, grow functional vessels (where they previously did not grow) and repair lymphatic damage caused by surgery, radiotherapy, tissue trauma and other diseases/disorders.
There are proteins that circulate in the body called vascular endothelial growth factors (one is VEGF-A for short). When VEGF-A meets a special receptor (in this case VEGFR-1 or 2), blood vessels grow. However, too much growth can be bad (as occurs in tumors). Of course the opposite extreme can also be bad – undergrowth or poorly organized growth – which results in insufficient functional vessels to supply cell and tissue demands.
There are also growth factors (VEGF-C and D) and their receptors (VEGFR-2 and 3) in the lymphatic vessels. As in the blood vascular system, high levels of these factors may be associated with higher risk of tumor spread. Lower levels of these growth factors may be associated with hypoplastic conditions such as primary lymphoedemas. The importance of VEGF-C and D in the sprouting and guidance in the migration of lymphatic vessels is crucial; if levels are low then growth is poor.
There are some indications of an anti-VEGFR-3 neutralising antibody which seems to be able to inhibit lymph vascular regeneration. This will be fantastic in situations where there is pathological overgrowth such as Klippel-Trenauney syndrome and others. There are many actions and interactions between the range of growth factors and receptors and the endothelium of the lymph and vascular systems leading to significant debate about which system developed first (Wilting et al 2004). This part of the argument is far from settled, but it’s clear that when there are vascular issues there are often associated lymphatic ones as well (and vice versa!). So does it really matter which was first, as long as we have better identified the growth factors, their receptors and the switches?
Of course the whole issue is not as simple as this. Looking at it simplistically is often dangerous, but it can at least help us understand some of the inter-relationships between our genes on one extreme and the lymphatic system and cell and tissue health, and lymphoedema on the other. What will be important to help us make better clinical decisions will be a close look at the relationships between our clinical descriptions of the range of lymph vascular dysplasias which confront us (which most often are nothing more fancy than a description of what we see externally) and what is actually going on at the genetic, molecular and biochemical levels (Witte et al., 2003).
Also as suggested earlier, tied in with lymphatic vessel development issues are other dysfunctionalities such those indicated in the papers of Harvey et al and Harvey (2005) who indicated that the inactivation of a single allele of the homeobox gene (Prox1) could lead to adult onset obesity seemingly due to abnormal leakage from poorly structured lymph vessels. Maybe this is in part the reason for the unique increase in epifascial adiposity in middle and latter stage lymphoedema! Or course it might not be just this since lymph flow is slow in lymphoedemas and slow lymph flow (due to possible adipogenic factors in it) might also help in the deposition of fatty tissue!
We also need to consider the other crucial roles of the lymphatic system and associated structures in tumor metastases and specific immunity. High levels of VGEF-C and D correlate with high numbers of intra tumoral vessels and appear to increase tumor metastasis. (Well at least that is one view and others disagree!). Again a detailed genetic interrogation and the use of the tools of molecular biology will have a lot to offer our understanding in this area.
Even further along the pathway, we should have the genetic basis of how patients will respond to pharmacological treatment. Some time ago coumarin (Lodema) was used as a common treatment for lymphoedemas, however the discovery of significant hepatotoxity effects and possible linked death of some patients meant it was taken from the market. And yet now it seems that the problem of hepatotoxity could have been related to reductions in CYP2A6 activity (the major enzyme involved in coumarin metabolism). Individuals with poor CYP2A6 metabolisers metabolised coumarin via a cytotoxic pathway. There are multiple CYP2A6 variants and some of these are alleles which express the enzyme with reduced or no activity. Those who are homozygous for these alleles are poor metabolizers and thus are the ones possibly more susceptible to coumarin toxicity. (Farinola and Piller, 2007)
There are genetic factors (some of which remain to be clearly identified) which will affect the development of lymphoedema, its inter-relationship with vascular development and a wide range of other syndromes, and which may affect the response to pharmacological means to manage the lymphoedema. At the present time, we do not have an adequate understanding to intervene and achieve better outcomes for individuals. We do hope that soon we will be able to tailor medicines to a patient, based on what we know of their genetic presentation.
Researchers have begun to switch genes on and off to control growth of small capillary-like lymphatics as the work of Stacker, Achen and others have shown experimentally (Stacker et al., 2006). There are quite a few steps that still need to be perfected before we can apply this practically, but we are well on the way. One very interesting step will be the application of this knowledge to tissue engineering (Neumann et al., 2003). Once scientists have control over lymph vascular proliferation, they may be able to build three dimensional tissues with a functional lymph vascular system and have an array of not only lymphatic capillaries but also collectors and nodes (Piller, 2003).
Harvey (2005) has indicated our most important questions of the moment relate to the nature of the signals that separate the lymphatic and blood vasculature, why there are different responses of the superficial and visceral lymphatic networks to growth factors and which signals determine endothelial cell growth and its fate. In the meantime we must encourage and participate in further research into primary lymphoedemas and their associated syndromes and of how best to treat and manage them. But what we can all do today is to work toward early recognition and identification of these syndromes, initiate appropriate treatment, and at least show that we can have some control over them even if we have an incomplete knowledge of all the reasons for their presentation. Some of our current research strategies here in Australia involve measurement of the structural and functional changes of the lympho-vascular systems both generally and locally and early detection of their symptoms (such as subtle fluid accumulation through bio-impedance spectroscopy). In addition, we are looking at the functional status of the lymphatic system through lymphoscintigraphy, since it is the blood-tissue lymph interface, the pre-lymphatic fluid and the lymph which carry the signals, mediate the response and the site of action of every thing we have been talking about. Optimal flow, physio-chemical properties, and communication with other entities are crucial irrespective of all of the issues of genetic transcription or coding errors. We must recognize and react to physical and structural changes while we wait for our knowledge at the genomic and molecular level to reach the level of expertise where we can begin to seriously influence the development, structure and function of the lymphatic system.
Definitions
Angiodysplasia: Abnormal growth of the lymph and blood vessels
Distichiasis: Double row of eyelashes. Seen in lymphedema-distichaisis patients with a FOXC2 gene mutation and often associated with other congenital anomalies.
Choleostasis: Blockage or slowing of bile flow from liver.
Lymphangiectasia: Malformation and disorder of the lymphatic capillaries or collectors
Allele: A range of DNA codings which occupy a particular position on a chromosome, variation (mutation) of which leads to a range of different outward expressions.
FOXC2: A gene which is a member of the forkhead family; an important developmental gene.
Homeobox gene: Gene that encodes proteins and is very important developmentally.
Epifascial Adiposity: Accumulation of fat above the deep fascia of the limb possibly due to slow lymph flow (lymphoedema) or a malformed lymphatic system with microaneurysms (lipoedema)
Key References :
Farinola N, N Piller.(2007) CYP2A6 polymorphisms: Is there a role for pharmocogenomics in preventing coumarin induced hepatotoxity in lymphoedema patients? Pharmogenomics 8(2):151-158.
Harvey N. (2005) Embryonic Lymphatic Development: Recent Advances and Unanswered Questions. Lymphatic Research and Biology 3(3):157-165.
Erickson R. (2001) Lymphoedema-Distichiasis and FOXC2 gene mutations. Lymphology 34(1): 1.
Harvey N, RS Srinivasan, M Dillard, et al. (2005) Lymphatic vascular defects promoted by Prox1 haploinsuffficiency cause adult onset obesity. Nature Genetics Advance on Line Publication 18 th sept 2005 doi:10.1038/ng1642
Piller N. (2003) Literature watch: Tissue Engineering. Lymphatic Research and Biology 1(4):337-341.
Witte M, M Bernas, K Northup, C Witte.(2003) Molecular Lymphology and genetics of lymphedema-angiodysplasia syndromes In Text book of Lymphology (Foeldi, M, Foeldi, I and Kubik, S Eds) Urban and Fisher, Munich.
Newmann T, B Nicholson, J Sanders.(2003) Tissue engineering of perfused microvessels. Microvascular Res. 66:59-67.
Wilting J, M Papoutsi, J Bekcer.(2004) The lymphatic vascular system: Secondary or Primary? Lymphology 37(3):98-106.
Northup K, M Witte, CWitte. (2003) Syndromic classification of hereditary lymphoedema. Lymphology 36(3):162-189.
Chaft J, D Steckman, F Blei. (2003) Genetics of vascular anomalies: An update Lymphatic Research and Biology 1(4):283-289.
Stacker SA, RA Hughes, RA Williams, MG Achen (2006) Current Strategies for modulating lymphangiogenesis signalling pathways in human disease. Curr. Med. Chem., 13:783-792.
Professor Neil Piller
Director Lymphoedema Assessment Clinic
Flinders University and Medical Centre
President of 2009 International Society of Lymphology Congress
South Australia
neil.piller@flinders.edu.au
By Brian D. Lawenda, MD, and Tammy E. Mondry, DPT, MSRS, CLT-LANA
*Author Disclosure:
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government
Introduction
Radiation therapy has been an effective therapeutic modality in the management of both benign and malignant tumors for over a century. The science and technology surrounding the delivery of this targeted treatment has significantly improved our ability to not only control tumors, but to also minimize the untoward complications of irradiating normal tissues. Advances in radiation and surgical techniques have significantly decreased the incidence of debilitating lymphedema (LE); however, this side effect will continue to occur in all patients who undergo surgery and/or radiation therapy on lymphatic-rich tissues. In this article, we will briefly review the pathophysiology of radiation-induced LE and discuss some of the more common radiation treatment techniques and indications employed in the management of breast, gynecologic and prostate cancers.
Etiology of Radiation-Induced Lymphedema
Radiation causes acute and chronic effects in most soft tissue subtypes. These effects are mediated by a complex process involving hormonal and oxidative changes within the tissue microenvironment. These changes persist for years, leading to apoptosis, production of free radicals, and changes in gene expression. This causes increased fibrosis, and decreased vascular/lymphatic vessel organization and function. (1) LE occurs as a result of the late effects on the lymphatic vessels and soft tissues, which cause obstruction and mechanical dysfunction due to radiation and surgical changes. If these effects are allowed to progress, they can lead to chronic dermal congestion, fibrosis, decreased limb mobility, pain and paresthesias.
Radiation late-effects are dependent on multiple factors, including: radiation dose, volume of irradiated tissue, and the histologic components of the tissue radiated. (1) The variability in these factors makes the development of generalized statements, regarding radiation side effects, a more complicated matter.
Radiation is most commonly delivered using a small daily dose, called a fraction of radiation, 5-days per week for 1-8 weeks. This as well as the total or cumulative dose is dependent on the indication, site of disease, disease type and the patient’s performance status. Late tissue effects are more likely to develop when larger daily doses and/or higher total doses are delivered. This is due to the fact that irradiated soft tissues are less able to repair the ionizing effects of larger daily doses and/or larger total doses.
The amount of tissue volume irradiated is also an important factor in the development of both acute and late effects. Even small increases in the size of the radiation field can potentially lead to a greater than expected degree of soft tissue side effects because volume increases exponentially. As larger amounts of tissue are irradiated, the degree of vascular and lymphatic injury/dysfunction, obstruction and parenchymal inflammation increases. Over time, these injuries can overwhelm the endogenous repair mechanisms and collateral vasculature of the effected tissues leading to fibrosis and/or edema.
Lymph node bearing areas to include inguinal, axillary and pelvic lymph nodes are frequently irradiated during the treatment of many cancers. There are certain high-risk indications when the regional lymphatics need to be treated with both surgery and radiation therapy. Individually, these interventions create lymphatic obstruction/disruption; however, clinically evident LE may not occur. This incidence increases dramatically when these areas are subjected to both therapeutic modalities.
Radiation Therapy in the Management of Breast Cancer
Adjuvant breast irradiation is almost always recommended following any breast conserving surgery. The breast can either be radiated with whole breast irradiation (WBI) or partial breast irradiation (PBI) techniques. The tissue at risk for local recurrence of breast cancer is the entire anatomic extent of the breast. This extends superiorly to the clavicle, inferiorly to approximately 2 cm below the inframammary fold, laterally to the mid-axillary line, and medially to the mid-sternum. The standard of care for treating breast cancer after breast conserving surgery is WBI, which includes all ipsilateral tissues within these boundaries. (2) Radiation can be delivered with external beam radiation therapy (EBRT) using a linear accelerator and/or through implantable, temporarily placed radiation sources known as brachytherapy.
The vast majority of patients who receive WBI are treated with EBRT. This technique requires a course of treatment, frequently 6-7 weeks long of daily treatment, 5 times per week. The planning for EBRT begins with a session called a simulation, where the radiation oncologist physically marks the borders of the breast on the patient. The patient then undergoes a CT scan of the chest so that the marked borders, tumor cavity, chest wall and lungs can be identified on a computer planning system. Radiation dose and beam parameters are then calculated and placed into the treatment delivery computer, which tells the linear accelerator how to deliver the daily treatment.
During the treatment, the patients will not feel or sense the radiation, and they will usually not begin to experience any side-effects until 2-3 weeks into treatment. Many patients will develop mild fatigue, skin redness/hyperpigmentation, and increased breast sensitivity as the course of treatment progresses. In some patients, the skin will develop dry or moist desquamation by the end of treatment. These effects are self-limiting and usually resolve within weeks-to-months after the completion of therapy.
The regional lymphatics in the axilla, supraclavicular fossa and internal mammary chain are only irradiated in specific circumstances when there is an increased risk of lymph node involvement or recurrence. Patients who have non-invasive breast cancer are not prescribed radiation to these regional lymphatics, as the risk of lymphatic spread is very uncommon. Invasive breast cancer is treated more aggressively due to the increased risk of lymphatic spread.
A sentinel lymph node biopsy (SLNB) is a procedure where a radioactive and / or blue dye is injected into the breast tumor or cavity and is allowed to migrate to the first echelon node(s), called the sentinel node. If the patient has a SNLB and no metastatic cancer is found, the patient will not require any further lymphatic surgery or lymphatic radiation. If however, the sentinel node is positive for cancer, the patient will require a more extensive axillary lymph node dissection (ALND). This procedure has a higher incidence of upper extremity LE than SLNB, and thus is no longer recommended as the first-line surgery in the absence of clinically involved axillary nodes.
Although there are no long-term, randomized controlled outcome data comparing WBI versus PBI, many patients with small (<3cm), low-intermediate grade breast cancers are currently being offered PBI. The rationale for PBI is that the greatest risk of a localized recurrence is within 1-2 cm of the tumor bed. PBI can be delivered either using EBRT or brachytherapy. In PBI, only the tumor bed cavity and the immediately adjacent tissues are treated. Brachytherapy can be done with either implanted catheters or a balloon implant, which is placed into the tumor cavity. Patients are then either admitted for 4-5 days, in a radiation-shielded room, while the dose is delivered or they are treated as an outpatient, using a daily radiation delivery system. The clear advantage of using brachytherapy is the convenience for the patient. The patient undergoes radiation for 4-5 days as compared to the 6-7 week EBRT course. Prospective, non-randomized data demonstrate that, in well-selected patients, this technique offers excellent local control (>95%) and cosmetic outcome. (3)
Following mastectomy, some patients will be offered radiation therapy to the chest wall, scar and/or regional lymphatics. This is almost exclusively done using EBRT, for 6-7 weeks. The regional lymphatics are irradiated based on the same criteria as in the above-mentioned sections on breast conserving treatment.
LE is a common side effect of breast and/or regional nodal irradiation. The incidence of ipsilateral upper extremity LE increases with combined surgery and radiation to the regional lymphatics. The occurrence of lymphedema after a SLNB alone is 2.6 – 3.0 percent. (4, 5) With this patient population, the tumor location in the upper outer quadrant was identified as a risk factor for the development of lymphedema. (5) If an ALND is performed alone, the incidence rate of lymphedema rises. It has been reported that after a level I/II ALND the incidence of lymphedema of the upper arm was 14 percent, 12 percent in the forearm, and 16 percent in the hand utilizing a diagnostic scale of a circumference difference greater than 5 percent. (6) The incidence rate of upper extremity lymphedema after an ALND and / or radiation therapy ranges from 6.0 – 33.5 percent. (4, 7-14)
Although no randomized data have been published, there is a suggestion from the available literature that breast edema occurs much more commonly after WBI as compared with PBI. Breast lymphedema following WBI ranges from 8 to 25 percent in patients who undergo a limited ALND. (15) In a recent study, the use of whole breast intensity modulated radiation therapy (IMRT) has been shown to possibly decrease the risk of chronic breast edema from 30 percent down to 3 percent as compared with the conventional WBI techniques. (16) A three-year median follow-up after lumpectomy and PBI using EBRT found a zero percent rate of breast edema. (17) While reports on a four-year median follow up of patients undergoing lumpectomy and PBI using intraoperative electron beam therapy found a two percent (1 out of 47 patients) rate of breast edema . (18)
Breast lymphedema is an often-overlooked area of breast cancer treatment-related side effects. Breast edema occurs in 6 – 48 percent of patients after receiving surgery and radiation therapy for breast cancer. (12, 19, 20) The incidence rate of breast lymphedema after a lumpectomy alone is six percent. (19) This rate drastically increases with nodal dissection and radiation therapy. The incidence of breast lymphedema after a sentinel lymph node biopsy and radiation therapy is 23 percent; with an axillary lymph node dissection and radiation therapy is 35 percent in node negative patients; and 48 percent in node positive patients. (20)
Radiation Therapy in the Management of Gynecologic Malignancies
Cervical cancer. Radiation is commonly used as a definitive or adjunctive treatment in patients with cervical cancer. In addition to the cervix, uterus and paracervical tissues, the regional lymphatics are often included. These consist of paracervical, pelvic sidewall / obturator and external iliac nodes (and para-aortic nodes in more advanced disease.) Total abdominal hysterectomy (TAH), with or without a pelvic lymph node dissection (PLND), is the most common surgical procedure for the earliest stages of invasive cervical cancer. As the disease becomes more extensive, a radical hysterectomy (RH) is recommended. Adjuvant radiation therapy is offered in cases when there is an increased risk of recurrence after surgery (i.e. large and/or deeply invasive tumors, lymphovascular space invasion, positive surgical margin, involved lymph nodes and parametrium.) (21) This generally involves a 5-week course of EBRT, with or without chemotherapy, to the tumor bed and pelvic lymphatics.
Definitive radiation is often recommended when there is higher probability of requiring adjuvant radiation therapy after surgery. Studies have demonstrated a greater incidence of complications and side-effects from combined surgery and radiation to the pelvis than either modality alone. (21) A single therapeutic modality is therefore preferable. In cases where definitive radiation is recommended, EBRT and brachytherapy are commonly employed. Generally, 5-weeks of EBRT are delivered to the tumor, surrounding tissues and lymphatics. This is then followed by a series of brachytherapy sessions comprised of either one or two inpatient treatments, or 1-2 weeks of multiple outpatient treatments.
The EBRT technique is delivered using either opposing anterior/posterior beams or anterior/posterior and lateral beams. Some groups are using an EBRT technique, called intensity modulated radiation therapy (IMRT), to deliver highly conformal doses of radiation to the areas at risk. IMRT uses a complex computer treatment planning system that employs multiple non-opposing beams to “paint” defined radiation doses throughout the target volume. This technique seems to reduce the unintended side effects of radiation doses to non-target tissues such as small bowel, bladder, and rectum.
Acute radiation-related side effects often occur within the first 2-4 weeks of treatment, and may include: fatigue, skin redness, loose stools, urinary frequency and dysuria. Late effects manifest months-to-years after treatment, and may include: vaginal dryness and shortening, dyspareunia, radiation proctitis or cystitis, sacral plexopathy, changes in bowel function, and lower extremity LE.
The incidence in lower extremity LE following surgery and radiation therapy in the treatment of cervical cancer ranged from 21-49 percent. (22-24) In a retrospective study of early-stage cervical carcinoma treated with preoperative radiotherapy and radical hysterectomy, LE occurred during the first year in 21 percent of the patients. (22) In another retrospective study, cervical cancer patients were treated with radical surgery and postoperative radiation therapy with 31 percent of patients presenting with lower extremity LE. (23) Patients being followed over a ten year period after undergoing radical hysterectomy followed by postoperative radiotherapy for carcinoma of the uterine cervix presented with LE at an incidence rate of 42 percent at five years, and 49 percent at ten years. (24)
Endometrial cancer. Most cases of endometrial cancer are treated with surgery alone (TAH/BSO +/- pelvic and para-aortic lymph node sampling.) However, when the risk of pelvic nodal involvement or vaginal cuff recurrence exceeds 5-10%, adjuvant radiation therapy may be recommended. The pelvic nodes are treated using a 5-week EBRT course. As with cervical cancer, some groups are using IMRT instead of the conventional opposed field radiation. The vaginal cuff (apex of the vagina) is treated using a series of outpatient brachytherapy sessions or a single inpatient session. (25)
When EBRT is used, the acute radiation-related side effects are similar to those mentioned above for cervical cancer. The use of vaginal cuff brachytherapy alone can lead to the development of acute radiation side effects, but skin redness does not occur because no external radiation beams traverse the skin. Fatigue, genitourinary and gastrointestinal side effects are less frequent due to the very short range of the brachytherapy radiation dose. Late effects from EBRT may include: vaginal dryness and shortening, dyspareunia, radiation proctitis or cystitis, changes in bowel function, and lower extremity LE. A retrospective review of 517 endometrial cancer patients undergoing surgery and postoperative radiotherapy reported LE of the lower extremity as a complication in 11 percent of all cases. (26) Vaginal cuff brachytherapy-alone can cause late vaginal cuff fibrosis, vaginal shortening, dryness and dyspareunia; rarely, vaginal cuff necrosis can also occur.
Vulvar cancer. EBRT is commonly the definitive therapeutic modality in the management of invasive vulvar cancer. The inguinal lymph nodes are the primary echelon drainage from tumors of this region and are often treated in this disease. Patients may undergo a superficial inguinal LND and/or radiation to these lymphatics. Typically, radiation is delivered with a combination of opposing anterior and posterior beams; however non co-planar (IMRT) beams may be used instead.
The acute effects of radiation usually occur within the first 2-3 weeks of treatment, and often include: skin redness, desquamation, dysuria, urinary frequency, loose stools, and proctitis. The late effects often manifest months-to-years later and include: vaginal dryness, dyspareunia, vaginal and anal stenosis (from soft tissue fibrosis), rectal urgency and other bowel movement changes. Both radiation and lymph node dissection can individually cause lower extremity LE, but the combination of the two substantially increases this risk. A retrospective review of patients undergoing bilateral groin irradiation for vulvar cancer revealed a LE incidence rate of 6 percent, as compared to 12 percent of patients undergoing bilateral or unilateral inguinofemoral dissection. (27)
Radiation Therapy in the Management of Prostate Cancer
Prostate cancer is commonly treated with either surgery (prostatectomy +/- pelvic LND) or radiation therapy (EBRT or brachytherapy.) The choice of treatment is based on a variety of factors, including: age, performance status, stage of disease, tumor grade, and prostate-specific antigen (PSA). In both management approaches of radiation or surgery, the entire prostate is treated or removed.
Radiation therapy targets the prostate only and not the lymphatics when the risk of lymph node involvement is less than 15%, whereas the pelvic lymphatics are often included when the risk exceeds 15%. The radiation fields are commonly delivered from multiple beam angles, using the non-coplanar IMRT technique. IMRT allows a higher dose to be delivered to the prostate (+/- pelvic LNs), while minimizing the dose received by the adjacent non-target tissues such as small bowel, rectum, bladder, and femurs. In circumstances where the patient either has a positive surgical margin and / or a rising postoperative PSA, adjuvant radiation therapy to the prostate bed is frequently recommended. The lymphatics are generally not intentionally treated in these circumstances.
The incidence of post irradiation lymphedema was found to be strongly dependent upon the extent of dissection performed to include biopsy only, limited / diagnostic dissection, or complete / therapeutic dissection. (28) Patients undergoing limited / diagnostic dissection followed by pelvic irradiation have a 25-30 percent risk of developing lymphedema; versus a 66 percent risk in patients undergoing complete / therapeutic dissection followed by pelvic irradiation. (28)
Conclusion
Radiation-induced LE is an untoward complication of treatment to the lymphatics as part of the management of many common malignancies. This article briefly reviewed some of the indications, techniques and side effects of radiation therapy as they pertain to a few of the more frequently encountered oncologic tumors.
All patients undergoing surgery and/or radiation therapy for the treatment of these cancers are at risk for the development of secondary lymphedema. Pre-treatment patient evaluation and education regarding lymphedema risk reduction practices should be performed. If lymphedema does develop CDT is a viable therapy for the treatment and maintenance of the condition.
1. Constine L, Milano M, Friedman D, et al. Late Effects of Cancer Treatment on Normal Tissues. In: Halperin E, Perez C, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 320-354.
2. NCCN. Practice Guidelines in Oncology (v.2.2008), Invasive Breast Cancer: Principles of Radiation Therapy. In; 2008.
3. Haffty B, Buchholz T, Perez CA. Early Stage Breast Cancer. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Therapy. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 1175-1291.
4. Golshan M, Martin W, Dowlatshahi K. Sentinel lymph node biopsy lowers the rate of lymphedema when compared with standard axillary lymph node dissection. . The American Surgeon 2003;69(3):209-211.
5. Sener SF, Winchester, D. J., Martz, C. H., Feldman, J. L., Cavanaugh, J. A., Winchester, D. P., Weigel, B., Bonnefoi, K., Kirby, K., & Morehead, C. . Lymphedema after sentinel lymphadenectomy for breast carcinoma. . Cancer 2001;92(4):748-752.
6. Querci della Rovere G, Ahmad, I., Singh, P., Ashley, S., Daniels, I. R. & Mortimer, P. An audit of the incidence of arm lymphoedema after prophylactic level I/II axillary dissection without division of the pectoralis minor muscle. . Annals of the Royal College of Surgeons of England 2003;85(3):158-161.
7. Wilke LG, McCall, L. M., Posther, K. E., Whitworth, P. W., Reintgen, D. S., Leitch, A. M., Gabram, S. G., Lucci, A., Cox, C. E., Hunt, K. K., Herndon, J. E. 2nd, & Giuliano, A. E. . Surgical complications associated with sentinel lymph node biopsy: Results from a prospective international cooperative group trial.. Annals of Surgical Oncology 2006;13(4):491-500.
8. Edwards TL. Prevalence and aetiology of lymphoedema after breast cancer treatment in southern Tasmania. The Australian and New Zealand Journal of Surgery 2000;70(6):412-418.
9. Logan V. Incidence and prevalence of lymphedema: A literature review. Journal of Clinical Nursing 1995;4(4):213-219.
10. Bani HA, Fasching, P. A., Lux, M. M., Rauh, B., Willner, M., Eder, I., Loehberg, C., Schrauder, M., Beckmann, M. W., & Bani, M. R. Lymphedema in breast cancer survivors: Assessment and information provision in a specialized breast unit. . Patient Education and Counseling 2007;66(3):311-318.
11. Hinrichs CS, Watroba, N. L., Rezaishiraz, H., Giese, W., Hurd, T., Fassl, K. A., & Edge, S. B. Lymphedema secondary to post mastectomy radiation: Incidence and risk factors. Annals of Surgical Oncology 2004;11(6):573-580.
12. Goffman TE, Laronga C, Wilson L, et al. Lymphedema of the arm and breast in irradiated breast cancer patients: risks in an era of dramatically changing axillary surgery. Breast Journal 2004;10(5):405-11.
13. Deo SV, Ray, S., Rath, G. K., Shukla, N. K., Kar, M., Asthana, S., & Raina, V. . Prevalence and risk factors for development of lymphedema following breast cancer treatment. Indian Journal of Cancer 2004;41(1):8-12.
14. Petrek JA, & Heelan, M. C. Incidence of breast carcinoma-related lymphedema. Cancer 1998;83(Supplement):2776-2781.
15. Meek AG. Breast radiotherapy and lymphedema. Cancer 1998;83(12 Suppl American):2788-97.
16. Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy. International Journal of Radiation Oncology, Biology, Physics 2007;68(5):1375-80.
17. Vicini FA, Chen P, Wallace M, et al. Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy. International Journal of Radiation Oncology, Biology, Physics 2007;69(4):1124-30.
18. Mussari S, Sabino Della Sala W, Busana L, et al. Full-dose intraoperative radiotherapy with electrons in breast cancer. First report on late toxicity and cosmetic results from a single-institution experience. Strahlentherapie und Onkologie 2006;182(10):589-95.
19. O'Brien PJ. Integrated survivorship care. . In: The Fourth Annual Orlando Breast Cancer Conference; 2007; Orlando, FL; 2007.
20. Ronka RH, Pamilo MS, von Smitten KA, et al. Breast lymphedema after breast conserving treatment. Acta Oncologica 2004;43(6):551-7.
21. Perez CA, Kavanagh B. Uterine Cervix. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 1532-1609.
22. Gerdin E, Cnattingius, S. & Johnson, P. . Complications after radiotherapy and radical hysterectomy in early-stage cervical carcinoma. Acta Obstetricia et Gynecologica Scandinavica 1995;74(7):554-561.
23. Hong JH, Tsai, C. S., Lai, C. H., Chang, T. C., Wang, C. C., Lee, S. P., Tseng, C. J. & Hsueh, S. . Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis. International Journal of Radiation Oncology, Biology, Physics 2002;53(5):1284-1290.
24. Chatani M, Nose, T., Masaki, N. & Inoue, T. . Adjuvant radiotherapy after radical hysterectomy of cervical cancer. Prognostic factors and complications. . Strahlentherapie und Onkologie 1998;174(10):504-509.
25. Cardenes H, Look K, Michael H, et al. Endometrium. In: Halperin E, Perez CA, Brady L, editors. Principles and Practice of Radiation Oncology. Fifth ed. Philadelphia: Lippincott, Williams and Wilkins; 2008. p. 1610-1628.
26. Nunns D, Williamson, K., Swaney, L. & Davy, M. The morbidity of surgery and adjuvant radiotherapy in the management of endometrial carcinoma. . International Journal of Gynecological Cancer 2000;10(3):233-238.
27. Petereit DG, Mehta, M. P., Buchler, D. A. & Kinsella, T. J. . A retrospective review of nodal treatment for vulvar cancer. . American Journal of Clinical Oncology 1993;16(1):38-42.
28. Pilepich MV, Asbell, S. O., Mulholland, G. S. & Pajak, T. Surgical staging in carcinoma of the prostate: The Radiation Therapy Oncology Group Experience. . Prostate 1984;5(5):471-476.
By Mei R. Fu, PhD, RN, ACNS-BC; Judith Haber, PhD, APRN-BC, FAAN; Amber A. Guth, MD, FACS; Deborah Axelrod, MD, FACS
Armer, J.M., Radina , M.E. , Porock, D., & Culbertson , S.D. (2003). Predicting breast cancer-related lymphedema using self-reported symptoms. Nursing Research, 52(6), 370-379.
American Cancer Society (ACS). (2006). Lymphedema: What Every Woman With Breast Cancer Should Know. http://www.cancer.org/docroot/MIT/content/Lymphedema_and_Breast_Cancer.asp Accessed on January 7, 2006.
National Lymphedema Network (NLN) (2006). Position Paper on Lymphedema Risk Reduction Practices. http://www.lymphnet.org/lymphedemaFAQs/positionPapers.htm Accessed on January 7, 2006.
National Cancer Institute (NCI). (2006). Lymphedema [Patient Version]. http://www.cancer.gov/search/results.aspx Accessed on January 7, 2006.
La nger, I. , Guller, U,. Berclaz, G., Koechli, O.R., Schaer, G., Fehr, M.K., Hess, T., Oertli, D., Bronz, L., Schnarwyler, B., Wight, E., Uehlinger, U., Infanger, E., Burger, D., Zuber, M. (2007). Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients. Annals of Surgery, 245 (3):452-61.
Paskett, E.D., Naughton, M.J., McCoy, T.P., Case, L.D., Abbott, J.M. (2007). The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiology, Biomarkers & Prevention, 16(4), 75-82.
Soran, A., D'Angelo, G., Begovic, M., Ardic, F., Harlak, A., Samuel, Wieand, H., Vogel, V.G., Johnson, R.R. (2006). Breast cancer-related lymphedema--what are the significant predictors and how they affect the severity of lymphedema? Breast Journal, 12(6), 536-543.
About Us | Privacy Policy |
Contact Us
©2005 National Lymphedema Network. All rights reserved.
Permission to print and duplicate this page for personal and educational purposes only, not for sale. Reprint Permission Request Form (pdf format, 86kb). For more information, call 510-208-3200.