Cancer Assciatin f Suth Africa (CANSA) Fact Sheet On Malignant Melanma Intrductin Malignant melanma (smetimes referred t as nly melanma) is the mst dangerus frm f skin cancer. These cancerus grwths develp when unrepaired DNA damage t skin cells (mst ften caused by ultravilet radiatin frm sunshine r tanning beds) triggers mutatins (genetic defects) that lead the skin cells t multiply rapidly and frm malignant tumurs. These tumurs riginate in the pigment-prducing melancytes in the basal layer f the epidermis. Melanmas ften resemble mles; sme develp frm mles. The majrity f melanmas are black r brwn, but they can als be skin-clured, pink, red, purple, blue r white. Melanma is caused mainly by intense, ccasinal UV expsure (frequently leading t sunburn), especially in thse wh are genetically predispsed t the disease. (Melanma Skin Cancer Fundatin). [Picture Credit: Melanma Picture] Incidence f Skin Cancer Amng Individuals f Clur Mst skin cancers are assciated with ultravilet (UV) radiatin frm the sun r tanning beds, and many peple f clur are less susceptible t UV damage thanks t the greater amunts f melanin darker skin prduces. Melanin is the prtective pigment that gives skin and eyes their clur, hwever, peple f clur can still develp skin cancer frm UV damage. Additinally, certain skin cancers are caused by factrs ther than UV - such as genetics r ther envirnmental influences - and may ccur n parts f the bdy rarely expsed t the sun. Fr example, darker-skinned peple are mre susceptible t acral lentiginus melanma (ALM), an especially virulent frm f melanma (the deadliest type f skin cancer) that typically appears n the palms f the hands and sles f the feet. Nvember 2017 Page 1
Acral lentiginus melanma (ALM) accunts fr abut 5% f melanma cases, and is a leading cause f skin cancer deaths. The disease initially appears as a bruise r nail streak n the skin. Mst patients d nt ntice ALM until it has already begun t spread aggressively thrughut the bdy. Bb Marley was killed frm this frm f malignant tumur under his tenail. ALM (als called subungual melanma) affects peple f Asian r African descent mre than any ther race r ethnicity. [Picture Credit: Acral Lentiginus Melanma] The average patient is between sixty and seventy years f age, but ALM can affect peple f any age. This classificatin f the disease is generally fund n the hands, feet and ther areas f the bdy where very little hair grws. Presently, sunlight is nt a prven cause f this cnditin. When the tumur is deeper than 1.0 mm r has spread t ther parts f the bdy thrugh the lymph ndes, the cancer frequently results in death. Different ethnicities are at higher risk fr particular skin malignancies: Latins, Chinese, and Japanese Asians tend t develp basal cell carcinma (BCC), the mst cmmn skin cancer. But the secnd mst cmmn, squamus cell carcinma (SCC), is mre frequent amng African Americans and Asian Indians. (Skin Cancer Fundatin; DermNet NZ; Knw Cancer). Cancer Percentage f All Cancers Asian Black Clured White Male Female Male Female Male Female Male Female Basal Cell Skin Cancer 5,85% 3,13% 3,06% 2,02% 20,55% 17,17% 38,97% 35,34% Squamus Cell Skin Cancer 2,73% 2,40% 3,58% 2,27% 8,15% 5,81% 15,23% 12,41% Malignant Melanma Skin Cancer 0,96% 0,46% 0,73% 1,06% 1,70% 1,64% 2,82% 3,11% (Natinal Cancer Registry, 2012). Incidence f Malignant Melanma in Suth Africa Accrding t the Natinal Cancer Registry (2013) the fllwing number f Malignant Melanma cases was histlgically diagnsed in Suth Africa during 2013: Grup - Males 2013 Actual N f Cases Estimated Lifetime Risk Percentage f All Cancers All males 819 1:183 2,28% Asian males 5 1:1 936 0,60% Black males 79 1:1 089 0,74% Clured males 71 1:219 1,71% White males 663 1:47 3,28% Nvember 2017 Page 2
Grup - Females 2013 Actual N f Cases Estimated Lifetime Risk Percentage f All Cancers All females 723 1:349 1,98% Asian females 13 1:568 1,27% Black females 138 1:1 401 0,88% Clured females 67 1:413 1,65% White females 506 1:72 3,18% The frequency f histlgically diagnsed cases f Malignant Melanma in Suth Africa fr 2013 was as fllws (Natinal Cancer Registry, 2013): Grup - Males 2013 0 19 20 29 30 39 40 49 50 59 60 69 70 79 80+ All males 4 17 54 110 152 236 157 83 Asian males 0 0 2 0 1 1 0 1 Black males 2 3 7 13 16 14 20 4 Clured males 0 2 4 12 13 17 19 4 White males 2 12 41 85 121 203 117 73 Grup - Females 2013 0 19 20 29 30 39 40 49 50 59 60 69 70 79 Year 80+ All females 4 20 73 119 149 125 127 94 Asian females 0 1 1 2 2 3 3 1 Black females 1 3 8 21 25 19 30 22 Clured females 0 0 5 13 13 9 12 13 White females 3 16 59 82 105 93 81 57 N.B. In the event that the ttals in any f the abve tables d nt tally, this may be the result f uncertainties as t the age, race r sex f the individual. The ttals fr all males and all females, hwever, always reflect the crrect ttals. Accrding t Krige (2010) there are distinct differences in malignant melanma between black and white ppulatins regarding the incidence, anatmical distributin, histgenetic types f melanma, stage at presentatin and prgnsis. In Suth Africa, the incidence f malignant melanma is 15 times less amng dark skinned individuals than in amng the white ppulatin. In fair r light-skinned ppulatins, mre than 90% f melanmas ccur in sun-expsed skin whereas 60% f melanmas amng Africans arise in nn-sun-expsed skin, invlving in particular, plantar, palmar, subungual (under the nail) and mucsal surfaces. The vlar and subungual areas are the mst cmmn anatmical sites f malignant melanma in black ppulatins, with 70% f malanmas fund n the lwer limb and 90% f melanmas n the leg ccurring belw the ankle. These views are supprted by Hudsn & Krige (1995). The ABCDE f Malignant Melanma Mles, brwn spts and grwths n the skin are usually harmless but nt always. Anyne wh has mre than 100 mles is at greater risk fr melanma. The first signs can appear in ne r mre atypical mles. That is why it is s imprtant t get t knw ne s skin very well and t recgnize any changes in the mles n yur bdy. Lk fr the ABCDE signs f melanma, and if yu see ne r mre, make an appintment with a physician immediately. (Melanma Skin Cancer Fundatin). Nvember 2017 Page 3
A - Asymmetry Shuld ne draws a line thrugh the picture f the mle n the right, the tw halves will nt match. B - Brder The brder f the mle n the right is uneven. The edges may be scallped r ntched. C - Clur Having a variety f clurs is anther warning signal. A number f different shades f brwn, tan r black culd appear. A melanma may als becme red, blue r sme ther clur. D - Diamater Melanmas usually are larger in diameter than the size f the eraser n an rdinary pencil (6 mm), but may smetimes be smaller when first detected. E - Evlving Any change in size, shape, clur, elevatin, r anther trait, r any new symptm such as bleeding, itching r crusting pints t danger. (Skin Cancer Fundatin). Other warning signs are: A sre that des nt heal A new grwth Spread f pigment (clur) frm the brder f a spt t surrunding skin Redness r a new swelling beynd the brder Change in sensatin itchiness, tenderness, r pain Change in the surface f a mle scaling, zing, bleeding, r the appearance f a bump r ndule (University f Califrnia, San Francisc). Metastatic Melanma "Metastatic" means that the melanma has spread t ne r mre parts f ne s bdy. It is als referred t as advanced r Stage IV Melanma. Nvember 2017 Page 4
Althugh it cannt be cured, it can be treated. Melanma starts in the cells that make melanin, the pigment that gives clur t ne s skin. It can spread anywhere in the bdy, but it first tends t g t the lymph ndes (a netwrk f glands that fight infectin) near where it frmed. Frm there it can travel t rgans like the brain, lungs, liver, and bnes, as well as ther areas f the skin -- including places far away frm where it started (what dctrs call the primary site ). Causes f Melanma - the sun s ultravilet (UV) rays are the main cause. Artificial sunlight (such as frm tanning beds) can als trigger it. UV radiatin damages the DNA in skin cells, prmpting them t multiply rapidly and becme cancer. Melanma can happen after intense UV expsure (think f very bad sunburns), especially in peple whse genes put them at risk fr the disease. But it can als happen due t everyday UV expsure, withut burning, ver a lng time. Anyne can get melanma, including peple with dark skin. It is mre likely if ne is white, especially if ne has light hair and eyes One has had many blistering sunburns, especially as a child r teenager One has several large r many small mles, including beauty marks and brwn blemishes Unusual mles run in ne s family If anyne in ne s family has already had any type f skin cancer One s immune system is weak Parts f the Bdy Affected by Melanma - melanma is ften fund n the belly, back, head, r neck in men, and n the arms and legs in wmen. But it can happen anywhere n the skin, including places that ne might nt expect, like the palms f ne s hands, fingernails, the bttms f ne s feet, scalp, and even the genitals. Symptms - melanmas ften resemble mles, and sme develp frm mles. Mst are black r brwn, but they can als be skin-clured, pink, red, purple, blue, r white. Smetimes a change t an existing mle r t nrmal skin is the first warning sign f advanced melanma. Other clues depend n where the cancer has spread t: Lymph ndes - they may feel hard, swllen, and painful Skin - ne may ntice hardened lumps under ne s skin Lungs - ne may be breathless r have a cugh that des nt get better Liver - ne may feel pain in the right side f the belly (under the lwer right ribs) r nt have ne s usual appetite Bnes - ne may feel an ache in ne s bnes Brain - warning signs may include a headache that des nt g away, weakness r numbness in ne s arms r legs, seizures, and changes in the persnality r md Nvember 2017 Page 5
Other symptms can include unexpected weight lss, and feeling very tired r nt well in general. All f these symptms can be caused by ther cnditins, s it is imprtant t see a dctr t find ut what is ging n. (Medscape). Screening fr Malignant Melanma Cnsider the fllwing screening ptins: Skin examinatins by a trained prfessinal - during the skin examinatin the prfessinal persn will cnduct a head-t-te inspectin f the skin. This may include an examinatin with the use f a Dermascpe. This type f examinatin is currently ffered by the Cancer Assciatin f Suth Africa (CANSA). Skin examinatins dne at hme - a self-examinatin may help in determining where mles, freckles and ther skin marks are n the skin. One can then, n a regular basis, inspect ne s skin with the purpse f nticing any changes. It is best t d this standing in frnt f a full-length mirrr while using a hand-held mirrr t inspect hard-t-see areas. Be sure t check the frnts, backs and sides f the arms and legs. In additin, check the grin, scalp, fingernails, sles f the feet and spaces between the tes. It is ften helpful t get a family member t assist in checking hard-t-see areas. (May Clinic). Increased Risk f Melanma fllwing Breast Cancer Diagnsis Individuals wh have had breast cancer has an increased risk fr melanma. Recent research shws a 29 percent excess risk fr melanma in breast cancer patients, as fund in the largest grup study f ver 500,000 breast cancer patients. Higher-risk still were breast cancer patients age 50 r yunger, wh in a study by Gggins, et al, had a 46 percent higher risk f melanma after breast cancer (Skin Cancer Fundatin). Hw Ultravilet (UV) Radiatin Triggers Melanma A prtein that immune cells use t cmmunicate with each ther is invlved in the develpment f melanma, a new study shws. The findings ffer fresh insight int hw melanma may develp in sme patients and suggest a new ptential target fr treatment. Melanma is an aggressive skin cancer that ften resists drug treatment. It arises when pigment-prducing skin cells, called melancytes, becme cancerus. Unfrtunately, melanma is becming mre cmmn every year. Studies have shwn that expsure t ultravilet (UV) radiatin frm the sun increases ne s risk f getting melanma, especially if ne has had sunburns during childhd. Over the last several years, a team f scientists has used genetically engineered mice t cnfirm the link between UV and melanma. In the study the researchers set ut t determine what changes take place when melancytes are expsed t UV radiatin. The scientists develped mice whse melancytes expressed a green flurescent prtein. The cells culd then be easily tracked in the muse and purified frm the skin. Nvember 2017 Page 6
The team expsed the mice t levels f UV radiatin that wuld nrmally cause sunburn in peple. They saw greater numbers f melancytes in the skin afterward, and the cells migrated tward the uter skin layer. Analysis f the cells shwed that they expressed a set f genes knwn t respnd t a prtein called interfern-gamma (IFN-g). These changes did nt ccur when the researchers blcked IFN-g in the mice, suggesting that this prtein is invlved in activating melancytes upn expsure t UV radiatin. The finding is surprising because IFN-g had previusly been thught t cntribute t the bdy s defenses against cancer. The scientists figured ut that the IFN-g came frm immune cells called macrphages, which entered the skin upn UV expsure. When the team mixed these UV-elicited macrphages with melanma cells and transplanted them int muse skin, they saw increased grwth f tumurs. Hwever, macrphages taken frm mice that had nt been expsed t UV did nt prmte tumur grwth. The increased tumur grwth als disappeared when the researchers blcked IFN-g. Finally, the team lked at human melanma tumurs. They fund that 70% f them cntained macrphages prducing IFN-g. Taken tgether, these findings strngly suggest that IFN-g-prducing macrphages play a substantial rle in prmting UV-induced melanma. Therefre, treatments that blck IFN-g after sunburn might prevent melancytes frm becming cancerus. This discvery may change hw interferns are used in the clinic as anticancer agents. If applicable t humans, the findings raise the pssibility that targeting the IFN-g pathway may represent a nvel, less txic therapeutic alternative fr effective treatment f a subset f malignant melanma patients, wh currently have pr cure rates. (Natinal Institutes f Health). Diagnsing Malignant Melanma Smetimes malignant melanma can be detected simply by lking at the skin, but the nly way t accurately diagnse melanma is by ding a bipsy. In this prcedure, all r part f the suspicius mle r grwth is remved, and a pathlgist analyses the sample under a micrscpe. Bipsy prcedures used t diagnse malignant melanma include: Punch bipsy. During a punch bipsy, the dctr uses a tl with a circular blade. The blade is pressed int the skin arund a suspicius mle and a rund piece f skin is remved Excisinal bipsy. In this prcedure, the entire mle r grwth is remved alng with a small brder f nrmal-appearing skin Incisinal bipsy. With an incisinal bipsy, nly the mst irregular part f a mle r grwth is taken fr labratry analysis The dctr will discuss the type f skin bipsy prcedure necessary with each individual patient. Nvember 2017 Page 7
Stages f Malignant Melanma The stage f a melanma describes hw deep it has grwn int the skin, and whether it has spread. It is imprtant t knw hw deep the melanma has gne int the skin because dctrs use this t decide n the kind f treatment needed, the likely risk f the melanma cming back after treatment and whether mre tests are needed t see if the melanma has spread int lymph ndes clse t the riginal site f the melanma. Types f melanma staging systems Dctrs use a number f different systems and scales t describe the stages f melanma: The Clark scale lks at hw deep the melanma has gne int the different layers f the skin. This is a way f measuring hw deeply the melanma has grwn int the skin and which levels f the skin are affected. The different levels f the Clark scale and what it means: Level 1 is als called melanma in situ the melanma cells are nly in the uter layer f the skin (the epidermis) Level 2 means there are melanma cells in the layer directly under the epidermis (the papillary dermis) Level 3 means the melanma cells are thrughut the papillary dermis and tuching n the next layer dwn (the reticular dermis) Level 4 means the melanma has spread int the reticular r deep dermis Level 5 means the melanma has grwn int the layer f fat under the skin (subcutaneus fat) The Breslw scale measures the thickness f the melanma in the skin. Breslws Scale used t be the mst favured methdlgy as its simplistic terms gave a clear and cnsise summary as t the thickness f the skin lesin. After the tumur had been surgically remved, the labratry wuld measure it in millimetres with a very precise instrument called a micrmeter. As melanmas eventually invade deeper int the skin, Breslws Scale can determine the pssibility f whether malignant cells have spread t the lymph ndes yet by hw thick the tumur is. The chart fr Breslw's Scale fr melanma staging is as fllws: Breslw s Thickness Apprximate 5-Year Survival <1mm 95-100% 1 2 mm 80 96% 2.1 4mm 60 75% >4mm 50% (Cancer Research UK; SinCancer-Survivr.Cm; American Cancer Sciety). Nvember 2017 Page 8
TNM Staging f Malignant Melanma TNM stands fr Tumur, Nde, and Metastases. This staging system describes the size f a primary tumur (T), whether any lymph ndes cntain cancer cells (N) and whether the cancer has spread t anther part f the bdy (M). The T part f the TNM describes the thickness f the melanma (primary tumur) accrding t the Breslw scale. There are 5 stages f tumur size in melanma: Tis melanma cells are nly in the very tp layer f the skin surface T1 the melanma is less than 1 millimetre thick T2 the melanma is between 1 mm and 2 mm thick T3 the melanma is between 2 mm and 4 mm thick T4 the melanma is mre than 4 mm thick The T part f the TNM system is further divided int tw grups, a and b, depending n whether the melanma is ulcerated r nt. Ulcerated means that the cvering layer f skin ver the tumur is brken. The letter a means nt ulcerated and b means ulcerated. S, fr example, a melanma may be T3a r T3b. Ulcerated melanmas have a higher risk f spreading than thse which are nt ulcerated. There are 4 pssible stages describing whether cancer cells are in the nearby lymph ndes r lymphatic ducts N0 there are n melanma cells in the nearby lymph ndes N1 there are melanma cells in ne lymph nde N2 there are melanma cells in 2 r 3 lymph ndes N3 there are melanma cells in 4 r mre lymph ndes The N part f the stage is further divided int grups a, b and c. If the cancer in the lymph nde can nly be seen with a micrscpe (micrmetastasis) it is classed as a. But if there are bvius signs f cancer in the lymph nde (macrmetastasis) it is classed as b. The letter c means that there are melanma cells in small areas f skin very clse t the primary melanma r in the skin lymph channels. These grups f melanma cells in the skin are called satellite metastases. Melanma cells in the lymph channels are called in transit metastases. M0 means the cancer has nt spread t anther part f the bdy. M1 means the cancer has spread t anther part f the bdy. Nvember 2017 Page 9
M1 is further divided int: M1a melanma cells have spread t skin in ther parts f the bdy r t lymph ndes far away frm the where the melanma started grwing M1b melanma cells have spread t the lung M1c melanma cells have spread t ther rgans r cause high bld levels f a chemical made by the liver (lactate dehydrgenase) In a very small number f peple, after a melanma has been remved, ndules f melanma may appear in the skin clse t the area f the riginal melanma. This is called lcal recurrence. It ccurs when sme melanma cells have brken away frm the primary tumur and begun t grw new tumurs (ndules) in the surrunding skin. This can happen at any time after the riginal melanma has been remved. S it culd be sme years later. The mre time that has gne by since yur riginal diagnsis, the less likely this is t happen. (Cancer Research UK). Where Melanma may Spread t in the Bdy Shuld Melanma spread (metastasise) it will mst prbably spread as indicated belw: Cancer Type: Bladder Breast Cln Clrectal Kidney Lung Melanma Ovary Pancreas Prstate Stmach Thyrid Uterus Nn-melanma skin cancer (Natinal Cancer Institute) Main Sites f Metastasis (Spread) Bne, liver, lung Bne, brain, liver, lung Liver, lung Liver, lung, peritneum (lining f abdmen) Adrenal gland, bne, brain, liver, lung Adrenal gland, bne, brain, liver, ther lung Bne, brain, liver, lung, skin, muscle Liver, lung, peritneum (lining f abdmen) Liver lung, peritneum (lining f abdmen) Adrenal gland, bne, liver, lung Liver, lung, peritneum (lining f abdmen), varies Bne, liver, lung Bne, liver, lung, peritneum (lining f abdmen), vagina Very rare: lymph ndes, lung, bne (if in head/neck regin) Treatment f Malignant Melanma The best treatment fr each individual patient depends n the stage f the malignant melanma, age and verall health f the patient. Treating early-stage melanmas Treatment fr early-stage melanmas usually includes surgery t remve the melanma. A very thin melanma may be remved entirely during the bipsy and require n further treatment. It may, hwever, be necessary fr the dctr t remve the melanma as well as a small brder f nrmal skin and a layer f tissue beneath the skin. Fr peple with earlystage melanmas, this may be the nly treatment needed. Nvember 2017 Page 10
Treating melanmas that have spread beynd the skin If the melanma has spread beynd the skin, treatment ptins may include: Surgery - surgery is used t remve affected lymph ndes. If the melanma has spread t nearby lymph ndes, the surgen may remve the affected ndes. Other additinal treatments, befre r after surgery, may als be recmmended by the treating dctr. New treatments fr skin cancer are appearing and evlving rapidly in recent years. Hwever, ne surgical technique has mre than std the test f time. Develped by Dr. Frederick Mhs in the 1930s, Mhs micrgraphic surgery has, with a few refinements, cme t be embraced ver the past decade by an increasing number f surgens fr an ever-widening variety f skin cancers. Tday, Mhs surgery has cme t be accepted as the single mst effective technique fr remving Basal Cell Carcinma (BCC) and Squamus Cell Carcinma (SCC), the tw mst cmmn skin cancers. It accmplishes the nifty trick f sparing the greatest amunt f healthy tissue while als mst cmpletely expunging cancer cells; cure rates fr BCC and SCC are an unparalleled 98 percent r higher with Mhs surgery, significantly better than the rates fr standard excisin r any ther accepted methd. [Picture Credit: Mhs Surgery 1] The reasn fr the technique's success is its simple elegance. Mhs surgery differs frm ther techniques in that micrscpic examinatin f all excised tissues ccurs during, rather than after the surgery, thereby eliminating the need t estimate hw far ut r deep the rts f the skin cancer g. This allws the Mhs surgen t remve all f the cancer cells while sparing as much nrmal tissue as pssible. The prcedure entails remving ne thin layer f tissue at a time; as each layer is remved, its margins are studied under a micrscpe fr the presence f cancer cells. If the margins are cancer-free, the surgery is ended. If nt, mre tissue is remved frm the margin where the cancer cells were fund, and the prcedure is repeated until all the margins f the final tissue sample examined are clear f cancer. In this way, Mhs surgery eliminates the guesswrk in skin cancer remval, prducing the best therapeutic and csmetic results. [Picture Credit: Mhs Surgery 2] In the past, Mhs surgery was rarely chsen fr Malignant Melanma surgery fr fear that sme micrscpic melanma cells might be missed and end up spreading arund the bdy (metastasising). Hwever, effrts t imprve the Mhs surgen's ability t identify melanma cells have led t special stains that highlight these cells, making them much easier t see under the micrscpe. Thus, mre Mhs surgens are nw using Nvember 2017 Page 11
this prcedure with certain melanmas. With the rates fr melanma and ther skin cancers cntinuing t skyrcket, Mhs surgery will play an ever mre imprtant rle in the cming decades. (Skin Cancer Fundatin). Chemtherapy - chemtherapy uses drugs t destry the cancer cells. Chemtherapy can be given intravenusly, in pill frm r bth s that it travels thrughut the bdy. Chemtherapy can be given via a vein in the arm r leg in a prcedure called islated limb perfusin. During this prcedure, bld in the arm r leg is nt allwed t travel t ther areas f the bdy fr a shrt time s that the chemtherapy drugs travel directly t the area arund the melanma and d nt affect ther parts f the bdy. Radiatin therapy - this treatment uses high-pwered energy beams, such as X-rays, t kill cancer cells. It is smetimes used t help relieve symptms f melanma that has spread t anther rgan. Fatigue is a cmmn side effect f radiatin therapy, but energy usually returns nce the treatment is cmplete. Bilgical therapy - bilgical therapy bsts the immune system t help the bdy fight the cancer. These treatments are made f substances prduced by the bdy r similar substances prduced in a labratry. Bilgical therapies used t treat melanma include interfern and interleukin-2. Side effects f these treatments are similar t thse f the flu, including chills, fatigue, fever, headache and muscle aches. Ipilimumab (Yervy) is anther drug that uses the immune system t fight the melanma. Ipilimumab is used t treat advanced melanma that has spread beynd its riginal lcatin. Targeted therapy - targeted therapy uses medicatins designed t target specific vulnerabilities in cancer cells. Vemurafenib (Zelbraf) is a targeted therapy apprved t treat advanced melanma that can't be treated with surgery r melanma that has spread thrugh the bdy. Vemurafenib nly treats melanma that has a certain genetic mutatin. Cells frm yur melanma can be tested t see whether this treatment may be an ptin fr yu. Experimental melanma treatments Clinical trials are studies f new treatments fr melanma. Dctrs use clinical trials t determine whether a treatment is safe and effective. Peple wh enrll in clinical trials have a chance t try evlving therapies, but a cure is nt guaranteed. And smetimes the ptential side effects are als nt knwn. Sme melanma treatments being studied in clinical trials include: New cmbinatins f treatments. Researchers are testing whether cmbining treatments may increase the effectiveness f melanma treatment. Fr instance, different cmbinatins f chemtherapy, bilgical therapy, targeted therapy and radiatin have been prpsed. Hwever, cmbining treatments can make severe side effects mre likely New targeted therapies. Researchers are testing new targeted medicatins in peple with advanced melanma. Fr instance, targeted drugs designed t stp melanma Nvember 2017 Page 12
frm attracting bld vessels have shwn sme success. Bld vessels carry nutrients t the melanma, and bld vessels help spread cancer cells thrughut the bdy. A drug that stps this prcess culd cause a melanma t remain small and lcalised Vaccine treatment. Vaccines fr treating cancer are different frm vaccines used t prevent diseases. Vaccine treatment fr melanma might invlve injecting altered cancer cells int the bdy t draw the attentin f the immune system (May Clinic; American Cancer Sciety; Cancer Research UK). New Malignant Melanma Treatment Currently in Clinical Trials Accrding t Prfessr Peter Jhnsn, chief clinician at Cancer Research UK, the newest treatment f malignant melanma is just at the beginning f a new era f cancer treatments using the immune system. The new treatment is said t turn the bdy's wn defences against a tumur and are starting t shw real prmise fr melanma and ther types f cancer. The new treatment cntains tw types f drug - ipilimumab (knwn as ipi) and anti-pd1s which break dwn the defences f cancer cells and are still in clinical trials. Accrding t the researchers dctrs can effectively rebt a patient's immune system by cmbining the tw drugs. This new cmbinatin f drugs culd mean mre than half are cured f the deadly cnditin. Advanced melanma culd becme a curable disease fr perhaps mre than 50% f patients within five t 10 years shuld the clinical trials be successful. (Cancer Research UK). Reducing the Risk fr Malignant Melanma Many cases f skin cancer, including malignant melanma, can be prevented by fllwing the fllwing precautins: Avid midday sun. Avid the sun when its rays are the strngest. Fr mst places, this is between abut 10 a.m. and 4 p.m. Because the sun's rays are strngest during this perid, try t schedule utdr activities fr ther times f the day, even in winter r when the sky is cludy. Yu absrb UV radiatin year-rund, and cluds ffer little prtectin frm damaging rays. Use a gd quality sunscreen. Use a brad-spectrum sunscreen, preferably ne with the CANSA Seal f Recgnitin. Refer t the CANSA Fact Sheet n Slar Radiatin and Skin Cancer fr detailed infrmatin regarding sunscreens. Apply the sunscreen generusly, and reapply every tw hurs r mre ften when swimming r perspiring. Use a generus amunt f sunscreen n all expsed skin, including the lips, the tips f the ears, and the backs f the hands and neck. Wear prtective clthing. Sunscreens dn't prvide cmplete prtectin frm UV rays, s wear tightly wven clthing that cvers yur arms and legs and a bradbrimmed hat, which prvides mre prtectin than a baseball cap r visr des. Sme cmpanies als sell phtprtective clthing. Yur dermatlgist can Nvember 2017 Page 13
recmmend an apprpriate brand. Dn't frget sunglasses. Lk fr thse that blck bth types f UV radiatin UVA and UVB rays. Avid tanning beds. Tanning beds emit UV radiatin, which can increase the risk f skin cancer. Becme familiar with the skin s changes can be nticed easily. If anything unusual is nticed, make an appintment with a dctr and pint it ut t him/her. Refer t the CANSA Fact Sheet n Slar Radiatin and Skin Cancer available n CANSA s Website: www.cansa.rg.za The Genetics f Melanma Genes carry infrmatin in the frm f DNA within each cell f the human bdy. Researchers estimate that there are 30,000 different genes in each cell. Genes are packaged nt chrmsmes. There are 23 pairs f chrmsmes in each cell. One chrmsme f each pair is inherited frm the persn's father and ne frm the persn's mther. Genes cntrl hw a cell functins, including hw quickly it grws, hw ften it divides, and hw lng it lives. T cntrl these functins, genes prduce prteins that perfrm specific tasks and act as messengers fr the cell. Therefre, it is essential that each gene have the crrect instructins r "cde" fr making its prtein s that the prtein can perfrm the prper functin fr the cell. The Rle f genes in melanma Many cancers begin when ne r mre genes in a cell are mutated (changed), creating an abnrmal prtein r n prtein at all. The infrmatin prvided by an abnrmal prtein is different frm that f a nrmal prtein, which can cause cells t multiply uncntrllably and becme cancerus. A persn may either be brn with a genetic mutatin in all f their cells (germline mutatin) r acquire a genetic mutatin in a single cell during his r her lifetime. An acquired mutatin is passed n t all cells that develp frm that single cell (called a smatic mutatin). Smatic mutatins can smetimes be caused by envirnmental factrs, such as cigarette smke. Mst melanmas (abut 90%) are cnsidered spradic, meaning that the damage t the genes ccurs by chance after a persn is brn, and there is n risk f passing n the gene t a persn's children. An increased risk f melanma ccurs when specific gene mutatins are passed within a family frm generatin t generatin. Keep in mind that melanma itself is nt inherited; it is the increased risk f develping melanma that is inherited. Many peple wh have an increased risk f melanma never develp the disease; nly 10% f melanma runs in the family (Cancer.Net). Genetic Link between Malignant Melanma and Other Cancers Researchers have discvered links between malignant melanma and several ther cancers. These include: Nvember 2017 Page 14
Familial malignant melanma. There are at least three different genes have been linked t hereditary melanma. Families with mutatins in these genes may have multiple dysplastic nevi (flat mles that are irregular in shape r clr). Althugh dysplastic nevi are likely t be related t altered genes, the specific genes invlved have nt been identified. The assciatin f familial melanma and multiple dysplastic nevi is als smetimes called familial atypical multiple mle melanma (FAMMM) r atypical nevus syndrme. Families with inherited melanma may als have an increased risk f develping pancreatic cancer and pssibly ther cancers. Melanma-astrcytma syndrme. Peple with this rare cnditin have an increased risk f melanma and astrcytma (a type f brain tumr). The specific gene fr this cnditin is thught t be lcated n chrmsme 9. Families with bth melanma and astrcytma have been shwn t have changes in a gene called CDKN2A gene, which affects tumur grwth. Retinblastma. Retinblastma is a childhd eye tumur. Children with hereditary retinblastma have an increased risk f develping ther cancers as they grw lder, especially melanma (50 times mre likely than the general ppulatin). Other childhd cancers. Children with hereditary retinblastma als have a higher risk fr stesarcma (a type f bne cancer), ther sarcmas, leukemia, lymphma, lung cancer, and bladder cancer. Hereditary breast and varian cancer (HBOC) syndrme - wmen. HBOC is assciated with mutatins in the BRCA1 and/r BRCA2 (BRCA stands fr BReast CAncer). Wmen with HBOC have an increased risk f breast cancer and varian cancer. Peple with HBOC als have an increased risk f melanma, specifically peple wh have a mutatin n the BRCA2 gene. Hereditary breast and varian cancer (HBOC) syndrme men. Men with HBOC have an increased risk f breast cancer and prstate cancer. Peple with HBOC als have an increased risk f melanma, specifically peple wh have a mutatin n the BRCA2 gene. The Xerderma Pigmentsum grup D gene (XPD). It has been recently implicated in bth melanma and breast cancer. This gene is assciated with xerderma pigmentsum, an inherited skin cnditin in which sufferers are dangerusly vulnerable t ultravilet light (UV) expsure, and ften suffer multiple skin cancers, including melanma. Certain variatins in the XPD gene are mdestly assciated with heightened breast cancer risk, while thers are mdestly assciated with melanma in patients ver age 50. V600E BRAF Gene. A gene mutatin that ccurs in melanma and ther cancers has nw been detected in hairy cell leukemia (HCL), a rare cancer f the bld. The mutatin, called V600E, ccurs in the BRAF gene and appears t cntribute t the disease, researchers reprted recently in the New England Jurnal f Medicine. (Cancer.Net; Jemal, et al.; Natinal Cancer Institute). Abut Clinical Trials Clinical trials are research studies that invlve peple. These studies test new ways t prevent, detect, diagnse, r treat diseases. Peple wh take part in cancer clinical trials have an pprtunity t cntribute t scientists knwledge abut cancer and t help in the Nvember 2017 Page 15
develpment f imprved cancer treatments. They als receive state-f-the-art care frm cancer experts. Types f Clinical Trials Cancer clinical trials differ accrding t their primary purpse. They include the fllwing types: Treatment - these trials test the effectiveness f new treatments r new ways f using current treatments in peple wh have cancer. The treatments tested may include new drugs r new cmbinatins f currently used drugs, new surgery r radiatin therapy techniques, and vaccines r ther treatments that stimulate a persn s immune system t fight cancer. Cmbinatins f different treatment types may als be tested in these trials. Preventin - these trials test new interventins that may lwer the risk f develping certain types f cancer. Mst cancer preventin trials invlve healthy peple wh have nt had cancer; hwever, they ften nly include peple wh have a higher than average risk f develping a specific type f cancer. Sme cancer preventin trials invlve peple wh have had cancer in the past; these trials test interventins that may help prevent the return (recurrence) f the riginal cancer r reduce the chance f develping a new type f cancer. Screening - these trials test new ways f finding cancer early. When cancer is fund early, it may be easier t treat and there may be a better chance f lng-term survival. Cancer screening trials usually invlve peple wh d nt have any signs r symptms f cancer. Hwever, participatin in these trials is ften limited t peple wh have a higher than average risk f develping a certain type f cancer because they have a family histry f that type f cancer r they have a histry f expsure t cancer-causing substances (e.g., cigarette smke). Diagnstic - these trials study new tests r prcedures that may help identify, r diagnse, cancer mre accurately. Diagnstic trials usually invlve peple wh have sme signs r symptms f cancer. Quality f life r supprtive care - these trials fcus n the cmfrt and quality f life f cancer patients and cancer survivrs. New ways t decrease the number r severity f side effects f cancer r its treatment are ften studied in these trials. Hw a specific type f cancer r its treatment affects a persn s everyday life may als be studied. Where Clinical Trials are Cnducted Cancer clinical trials take place in cities and twns in dctrs ffices, cancer centres and ther medical centres, cmmunity hspitals and clinics. A single trial may take place at ne r tw specialised medical centres nly r at hundreds f ffices, hspitals, and centres. Each clinical trial is managed by a research team that can include dctrs, nurses, research assistants, data analysts, and ther specialists. The research team wrks clsely with ther health prfessinals, including ther dctrs and nurses, labratry technicians, pharmacists, dieticians, and scial wrkers, t prvide medical and supprtive care t peple wh take part in a clinical trial. Nvember 2017 Page 16
Research Team The research team clsely mnitrs the health f peple taking part in the clinical trial and gives them specific instructins when necessary. T ensure the reliability f the trial s results, it is imprtant fr the participants t fllw the research team s instructins. The instructins may include keeping lgs r answering questinnaires. The research team may als seek t cntact the participants regularly after the trial ends t get updates n their health. Clinical Trial Prtcl Every clinical trial has a prtcl, r actin plan, that describes what will be dne in the trial, hw the trial will be cnducted, and why each part f the trial is necessary. The prtcl als includes guidelines fr wh can and cannt participate in the trial. These guidelines, called eligibility criteria, describe the characteristics that all interested peple must have befre they can take part in the trial. Eligibility criteria can include age, sex, medical histry, and current health status. Eligibility criteria fr cancer treatment trials ften include the type and stage f cancer, as well as the type(s) f cancer treatment already received. Enrlling peple wh have similar characteristics helps ensure that the utcme f a trial is due t the interventin being tested and nt t ther factrs. In this way, eligibility criteria help researchers btain the mst accurate and meaningful results pssible. Natinal and Internatinal Regulatins Natinal and internatinal regulatins and plicies have been develped t help ensure that research invlving peple is cnducted accrding t strict scientific and ethical principles. In these regulatins and plicies, peple wh participate in research are usually referred t as human subjects. Infrmed Cnsent Infrmed cnsent is a prcess thrugh which peple learn the imprtant facts abut a clinical trial t help them decide whether r nt t take part in it, and cntinue t learn new infrmatin abut the trial that helps them decide whether r nt t cntinue participating in it. During the first part f the infrmed cnsent prcess, peple are given detailed infrmatin abut a trial, including infrmatin abut the purpse f the trial, the tests and ther prcedures that will be required, and the pssible benefits and harms f taking part in the trial. Besides talking with a dctr r nurse, ptential trial participants are given a frm, called an infrmed cnsent frm, that prvides infrmatin abut the trial in writing. Peple wh agree t take part in the trial are asked t sign the frm. Hwever, signing this frm des nt mean that a persn must remain in the trial. Anyne can chse t leave a trial at any time either befre it starts r at any time during the trial r during the fllw-up perid. It is imprtant fr peple wh decide t leave a trial t get infrmatin frm the research team abut hw t leave the trial safely. The infrmed cnsent prcess cntinues thrughut a trial. If new benefits, risks, r side effects are discvered during the curse f a trial, the researchers must infrm the participants s they can decide whether r nt they want t cntinue t take part in the trial. In sme cases, participants wh want t cntinue t take part in a trial may be asked t sign a new infrmed cnsent frm. Nvember 2017 Page 17
New interventins are ften studied in a stepwise fashin, with each step representing a different phase in the clinical research prcess. The fllwing phases are used fr cancer treatment trials: Phases f a Clinical Trial Phase 0. These trials represent the earliest step in testing new treatments in humans. In a phase 0 trial, a very small dse f a chemical r bilgic agent is given t a small number f peple (apprximately 10-15) t gather preliminary infrmatin abut hw the agent is prcessed by the bdy (pharmackinetics) and hw the agent affects the bdy (pharmacdynamics). Because the agents are given in such small amunts, n infrmatin is btained abut their safety r effectiveness in treating cancer. Phase 0 trials are als called micr-dsing studies, explratry Investigatinal New Drug (IND) trials, r early phase I trials. The peple wh take part in these trials usually have advanced disease, and n knwn, effective treatment ptins are available t them. Phase I (als called phase 1). These trials are cnducted mainly t evaluate the safety f chemical r bilgic agents r ther types f interventins (e.g., a new radiatin therapy technique). They help determine the maximum dse that can be given safely (als knwn as the maximum tlerated dse) and whether an interventin causes harmful side effects. Phase I trials enrl small numbers f peple (20 r mre) wh have advanced cancer that cannt be treated effectively with standard (usual) treatments r fr which n standard treatment exists. Althugh evaluating the effectiveness f interventins is nt a primary gal f these trials, dctrs d lk fr evidence that the interventins might be useful as treatments. Phase II (als called phase 2). These trials test the effectiveness f interventins in peple wh have a specific type f cancer r related cancers. They als cntinue t lk at the safety f interventins. Phase II trials usually enrl fewer than 100 peple but may include as many as 300. The peple wh participate in phase II trials may r may nt have been treated previusly with standard therapy fr their type f cancer. If a persn has been treated previusly, their eligibility t participate in a specific trial may depend n the type and amunt f prir treatment they received. Althugh phase II trials can give sme indicatin f whether r nt an interventin wrks, they are almst never designed t shw whether an interventin is better than standard therapy. Phase III (als called phase 3). These trials cmpare the effectiveness f a new interventin, r new use f an existing interventin, with the current standard f care (usual treatment) fr a particular type f cancer. Phase III trials als examine hw the side effects f the new interventin cmpare with thse f the usual treatment. If the new interventin is mre effective than the usual treatment and/r is easier t tlerate, it may becme the new standard f care. Phase III trials usually invlve large grups f peple (100 t several thusand), wh are randmly assigned t ne f tw treatment grups, r trial arms : (1) a cntrl grup, in which everyne in the grup receives usual treatment fr their type f cancer, r 2) an investigatinal r experimental grup, in which everyne in the grup receives the new interventin r new use f an existing interventin. The trial participants are assigned t their individual grups by randm assignment, r randmisatin. Randmisatin helps ensure Nvember 2017 Page 18
that the grups have similar characteristics. This balance is necessary s the researchers can have cnfidence that any differences they bserve in hw the tw grups respnd t the treatments they receive are due t the treatments and nt t ther differences between the grups. Randmisatin is usually dne by a cmputer prgram t ensure that human chices d nt influence the assignment t grups. The trial participants cannt request t be in a particular grup, and the researchers cannt influence hw peple are assigned t the grups. Usually, neither the participants nr their dctrs knw what treatment the participants are receiving. Peple wh participate in phase III trials may r may nt have been treated previusly. If they have been treated previusly, their eligibility t participate in a specific trial may depend n the type and the amunt f prir treatment they received. In mst cases, an interventin will mve int phase III testing nly after it has shwn prmise in phase I and phase II trials. Phase IV (als called phase 4). These trials further evaluate the effectiveness and lng-term safety f drugs r ther interventins. They usually take place after a drug r interventin has been apprved by the medicine regulatry ffice fr standard use. Several hundred t several thusand peple may take part in a phase IV trial. These trials are als knwn as pst-marketing surveillance trials. They are generally spnsred by drug cmpanies. Smetimes clinical trial phases may be cmbined (e.g., phase I/II r phase II/III trials) t minimize the risks t participants and/r t allw faster develpment f a new interventin. Althugh treatment trials are always assigned a phase, ther clinical trials (e.g., screening, preventin, diagnstic, and quality-f-life trials) may nt be labelled this way. Use f Placebs The use f placebs as cmparisn r cntrl interventins in cancer treatment trials is rare. If a placeb is used by itself, it is because n standard treatment exists. In this case, a trial wuld cmpare the effects f a new treatment with the effects f a placeb. Mre ften, hwever, placebs are given alng with a standard treatment. Fr example, a trial might cmpare the effects f a standard treatment plus a new treatment with the effects f the same standard treatment plus a placeb. Pssible benefits f taking part in a clinical trial The benefits f participating in a clinical trial include the fllwing: Trial participants have access t prmising new interventins that are generally nt available utside f a clinical trial. The interventin being studied may be mre effective than standard therapy. If it is mre effective, trial participants may be the first t benefit frm it. Trial participants receive regular and careful medical attentin frm a research team that includes dctrs, nurses, and ther health prfessinals. The results f the trial may help ther peple wh need cancer treatment in the future. Nvember 2017 Page 19
Trial participants are helping scientists learn mre abut cancer (e.g., hw it grws, hw it acts, and what influences its grwth and spread). Ptential harms assciated with taking part in a clinical trial The ptential harms f participating in a clinical trial include the fllwing: The new interventin being studied may nt be better than standard therapy, r it may have harmful side effects that dctrs d nt expect r that are wrse than thse assciated with standard therapy. Trial participants may be required t make mre visits t the dctr than they wuld if they were nt in a clinical trial and/r may need t travel farther fr thse visits. Crrelative research studies, and hw they are related t clinical trials In additin t answering questins abut the effectiveness f new interventins, clinical trials prvide the pprtunity fr additinal research. These additinal research studies, called crrelative r ancillary studies, may use bld, tumur, r ther tissue specimens (als knwn as bispecimens ) btained frm trial participants befre, during, r after treatment. Fr example, the mlecular characteristics f tumur specimens cllected during a trial might be analysed t see if there is a relatinship between the presence f a certain gene mutatin r the amunt f a specific prtein and hw trial participants respnded t the treatment they received. Infrmatin btained frm these types f studies culd lead t mre accurate predictins abut hw individual patients will respnd t certain cancer treatments, imprved ways f finding cancer earlier, new methds f identifying peple wh have an increased risk f cancer, and new appraches t try t prevent cancer. Clinical trial participants must give their permissin befre bispecimens btained frm them can be used fr research purpses. When a clinical trial is ver After a clinical trial is cmpleted, the researchers lk carefully at the data cllected during the trial t understand the meaning f the findings and t plan further research. After a phase I r phase II trial, the researchers decide whether r nt t mve n t the next phase r stp testing the interventin because it was nt safe r effective. When a phase III trial is cmpleted, the researchers analyse the data t determine whether the results have medical imprtance and, if s, whether the tested interventin culd becme the new standard f care. The results f clinical trials are ften published in peer-reviewed scientific jurnals. Peer review is a prcess by which cancer research experts nt assciated with a trial review the study reprt befre it is published t make sure that the data are sund, the data analysis was perfrmed crrectly, and the cnclusins are apprpriate. If the results are particularly imprtant, they may be reprted by the media and discussed at a scientific meeting and by patient advcacy grups befre they are published in a jurnal. Once a new interventin has prven safe and effective in a clinical trial, it may becme a new standard f care. (Natinal Cancer Institute). Nvember 2017 Page 20