Table A5.
Toxicity Details
| Study | Year | Local Therapy | Toxicity Grading Scale Listed | Details of Toxicity by Grade | Grade 3 or Higher or Severe Toxicity | Toxicities Reported | Toxicity Resolution |
|---|---|---|---|---|---|---|---|
| Heller et al | 1996 | ECT | NA | NA | 0 | Muscle contractions during each pulse, mild pain at treatment site during each pulse, slight burning of skin, muscle fatigue, fever, chills, nausea, general malaise by 24 to 48 hours after treatment | Pain resolved by 24 to 48 hours; burning of skin resolved by 2 to 4 weeks |
| Sersa et al | 2000 | ECT* | NA | NA | 0 | Muscle contractions, slight erythema, scab, minimal scarring, slight depigmentation | NA |
| Rodriguez-Cuevas et al | 2001 | ECT | NA | NA | 0 | Muscle contractions (well tolerated), fibrosis | NA |
| Byrne et al | 2005 | ECT | CALGB CTC, 1989 | NA | 0 | During ECT: electric shock sensation, muscle spasm, pain. Treated lesions: inflammatory reaction, superficial necrosis, eschar | All healed by 16 weeks post-treatment |
| Gaudy et al | 2006 | ECT* | NA | NA | NA | ECT causes discomfort and local pain in nine of 12 patients, and three of 12 myoclonus. Hematoma in two of 12. No systemic toxicity. | “No residual pain after treatment.” Complete healing median time, 2 weeks, one patient took 8 months to heal |
| Marty et al | 2006 | ECT | NA | NA | None related to treatment | Local pain, muscle contraction (> 78% of patients) | Pain reduced significantly by 2 days post-treatment |
| Quaglino et al | 2008 | ECT | NA | NA | 0 | Erythema, slight edema at treatment site in three patient; marks from electrodes, erosion in all cases | Local erythema resolved within a “few days,” and scars healed within 1 month |
| Matthiessen et al | 2011 | ECT | CTC v3 | NA | “No serious adverse events”; “no CTC grade 3 or 4 toxicity” | Flu-like symptoms (10%), pain for 1 to 2 days post-treatment (10%), ulceration (4%), cough (2%), allergic skin reaction (2%), anxiety (2%) | NA |
| Benevento et al | 2012 | ECT | NA | NA | NA | NA | NA |
| Campana et al | 2012 | ECT | CTCAE v3.0 | Local: grade 1, 20%; grade 2, 23%; grade 3, 14% | Grade 3 ulceration in five of 35 (many had ulcerative metastases at presentation) | Fever (16.1%), uncontrolled pain (5.7%), nausea/vomiting (n = 4), syncope (n = 1), urticaria (n = 1) | 77% had pain 7 days after ECT; 49% had pain 1 month after ECT |
| Kendler et al | 2013 | ECT | NA | NA | No serious adverse events | Pain requiring medication, cutaneous infection 7 days post-treatment (n = 1), superficial ulceration at 2 weeks (n = 1), burning sensation (n = 1) | Infection resolved within 3 days with antibiotics |
| Sperduto et al | 1991 | PDT | NA | NA | One patient needed skin flap | 100% had erythema, 95% had pain, 25% had blistering, 50% had necrosis, 20% had ulceration | NA |
| Cairnduff et al | 1994 | PDT | NA | NA | 0 | Sensations and discomfort during treatment including burning, prickling, or boring sensation. Edema, erythema, weeping for 1 to 2 weeks | All healed by 2 to 3 months |
| Baas et al | 1996 | PDT | NA | NA | 0 | Bluish/brown discoloration for first 24 hours, turned black with scab over next 10 days and remained for 8 weeks to 20 months. Rare local infection treated with topical or oral antibiotics, one burning sensation. | Most scabs resolved by 20 months |
| Kaplan et al | 1998 | PDT | NA | NA | NA | Transient facial swelling, deep eschar, erythema, necrotic lesions requiring debridement | Local swelling and eschar resolved by 1 month |
| Mang et al | 1998 | PDT | NA | NA | 0 | Chest wall pain ranged from 2 days to 3 weeks, one localized infection. Pain managed by oral medication. One patient had photosensitivity. All at 1 month had scab and larger lesions formed an eschar. Cosmetic results were excellent. | Local pain resolved by 3 weeks at the latest |
| Overgaard et al | 1985 | RT | Overgaard† | Moderate erythema (n = 7); severe erythema (n = 8) | Eight had severe erythema, but none had moist desquamation | Moderate and severe erythema, fibrosis | NA |
| Menendez et al | 2009 | RT | Listed grade 1 to 3 with no definitions | Grade 1, five of seven; grade 3, three of seven | Three of seven had ulceration | Ulceration | NA |
| Cohen et al‡ | 1978 | ILT | NA | NA | Three grade 4 “near fatality” from DIC | Fever 88%, chills 84%, nausea 40%, major ulceration 44%, cellulitis 16%, distant infection 8%, DIC 12% | NA |
| Cohen et al‡ | 1978 | ILT | NA | NA | 0 | Fever 0%, chills 0%, nausea 0%, major ulceration 4%, cellulitis 2%, distant infection 0%, DIC 0% | NA |
| Nathanson et al | 1979 | ILT | NA | NA | NA | Vomiting/diarrhea (n = 4), fever (n = 16), skin symptoms (n = 5), moderate leukopenia or thrombocytopenia (n = 4), moderate change in LFTs (n = 2), severe change in LFTs (n = 1) | NA |
| Cascinelli et al | 1993 | ILT | NA | NA | NA | NA | NA |
| Stewart et al§ | 1999 | ILT | Simply listed toxicity by grade 1, 2, 3 but no definition | Grade 2, one patient (pain and fever) | 0 | Local inflammation, injection site pain, fever, tissue necrosis | Inflammation resolved after 5 to 7 days |
| Stewart et al§ | 1999 | ILT | Simply listed toxicity by grade 1, 2, 3 but no definition | Grade 2, four patients (pain and fever) | 0 | Local inflammation, injection site pain, fever, cellulitis, joint pain, nausea, myalgia, hiccups | Inflammation resolved after 5 to 7 days |
| Hoeller et al | 2001 | ILT | WHO | Of 51 evaluable patients, 46 had grade 1 toxicity, six grade 2, one grade 3 | One had pain at injection site | Pruritus, erythema at injection site, ecchymoses, pain at injection site | NA |
| Stopeck et al | 2001 | ILT | NA | NA | NA | Mild drowsiness, local erythema, increase in WBC, increase in eosinophils | NA |
| Radny et al | 2003 | ILT | NCI CTC v2.0, 1999 | Overall: erythema 100%, swelling, necrosis 89%, erosion 75%, ulceration 75%, eschar 71%, bleeding 64%, pain 50% | “Severe”: erythema 46%, swelling 36%, necrosis 61%, erosion 21%, ulceration 43%, eschar 43%, bleeding 4%, pain 21% | Erythema, swelling, necrosis, erosion, ulceration, eschar, bleeding, pain | 6 to 31 weeks for resolution of local symptoms |
| Oratz et al | 2003 | ILT | WHO Criteria | Grade 1, 100%; grade 2, 54%; grade 3, 4% | Grade 3, 4% (n = 1) severe headache | Local erythema, fever, flu-like symptoms, pain, fatigue, nausea/vomiting, stomach pain, diarrhea, headache, muscle cramps, tachycardia | All had local erythema that resolved within days of treatment |
| Byrne et al | 2005 | ILT | CALGB CTC 1989 | NA | NA | Treated lesions: inflammatory reaction, superficial necrosis, eschar | All healed by 16 weeks post-treatment |
| Triozzi et al | 2005 | ILT | NCI CTC v2.0 | 23 grade 1; 19 grade 2; zero grade 3 to 4 | 0 | Inflammatory reactions at injection site, fever, chills, myalgia, fatigue, superficial vesicles/bullae | NA |
| Gonzalez et al | 2006 | ILT | NA | NA | NA | NA | NA |
| Kimata et al | 2006 | ILT | WHO 1979 | 95% grade 1 or 2 | One grade 3 event linked to treatment: abdominal pain | Injection site pain, fatigue, pyrexia, arthralgia, dizziness, headache, abdominal pain, vomiting, hemorrhage, hypotension, exacerbated dyspnea, erythema, skin ulcer, injection site edema/hypersensitivity, vasodilation, flatulence, ecchymosis, bone pain, increased cough, pneumonia, rhinitis, pruritus, rash, skin discoloration | NA |
| Gaudy et al | 2006 | ILT | NA | NA | 0 | No adverse effects from treatment occurred | NA |
| Dummer et al | 2008 | ILT* | NCI CTC v2.0 | “Most mild to moderate adverse events” | Seven “serious” events (thrombocytopenia, pleural effusion, lymphocytopenia, anemia | Injection site pain, increase in tumor pain, chills, fatigue, fever, nausea, vomiting, constipation, stomach pain, headache, asthenia, lymphocytopenia/thrombocytopenia, diarrhea | NA |
| Hofmann et al | 2008 | ILT | NCI CTC v2.0 | Grade 1, 16 events; grade 2, 12 events; grade 3, one event | One lymphopenia | Local swelling and erythema, fever, fatigue, rigors, headache, pain, increase in blood pressure, lymphocytopenia | Lymphopenia resolved in 14 days |
| Thompson et al | 2008 | ILT | NA | “No serious adverse events” | Mild to moderate injection site pain (n = 8), local inflammation (n = 4), pruritus (n = 3) | NA | |
| Bedikian et al | 2010 | ILT | NCI CTC v2.0 | Grade 1, 199 events; grade 2, 19 events; grade 3 to 4, zero events | 0 | Myalgia (n = 23), pyrexia (n = 22), arthralgia (n = 19), headache (n = 19), injection site pain (n = 43), injection site erythema (n = 28), rigors (n = 33), fatigue, nonspecific arthritis (n = 1) | NA |
| Weide et al | 2010 | ILT | CTC v3 | Grade 1, < 70% of patients; grade 2, < 60% of patients | 0 | Inflammatory injection site reaction (swelling, erythema locally), necrosis, injection pain, fever 58%, fatigue 36%, nausea 34%, stomach pain (n = 4), myalgia (n = 4), headache (n = 4), itching exanthem (n = 3), dry oral mucosa (n = 2), pruritus (n = 2), hair loss (n = 1), diarrhea (n = 1), urticaria (n = 1), atopic dermatitis worsening (n = 1), single episode mild cardiac arrhythmia (n = 1), vitiligo-like depigmentation around treated metastases (n = 1) | NA |
| Unger et al | 1992 | TT | WHO | Grade 1 erythema, four of 24; grade 2 erythema, one of 24 | 0 | Itching, slight erythema, scaling, dryness | NA |
| Unger et al | 1993 | TT | WHO | NA | 0 | Skin pruritus (two of 74), rash, dry skin, bleeding, and skin atrophy | NA |
| Terwogt et al | 1999 | TT | WHO | Grade 1, five; grade 2, 15; grade 3, one; unknown, one | One of 33 had “severe” skin reaction | 22 of 33 adverse skin reactions including dryness, erythema, itch, pain, desquamation. Nausea in two patients. | NA |
| Smorenburg et al | 2000 | TT* | WHO | Local: grade 1, nine; grade 2, two; systemic: grade 1, three; grade 2, one | No grade 3 or 4 local or systemic events | Skin atrophy (20%), exfoliation (15%), rash (10%), pruritus (10%), pain (15%), dry skin (10%), telangiectasis (5%), nausea/vomiting (5%), anorexia (5%), fatigue (5%) | NA |
| Leonard et al | 2001 | TT* | NCI CTC 1986 | Grade 1, three of 24; grade 2, 11 of 24; grade 3, four of 24; grade 4, four of 24 | Eight of 24 had “significant” to “severe” local skin reaction | Dryness, erythema, desquamation, local pain, burning, itching. Rare ulcerating dermatitis. | NA |
| Eilender et al | 2006 | TT* | CTC v2.0 | Total cohort (n = 27); grade 1 to 2, 10; grade 3 to 4, zero | 0 | Anemia, itching, burning, rash (most patients had no toxicity) | NA |
| Salazar et al | 2011 | TT* | CTCAE v3.0 | “Primarily grade 1 to 2 neutropenia, anemia, grade 1 skin toxicity” | NA | NA | NA |
| Florin et al | 2012 | TT | NA | NA | 0 | Local inflammation, ulceration, erythema | |
| Adams et al | 2012 | TT* | CTCAE v 3.0 | Local: grade 1, five of 10; grade 2, two of 10; systemic: grade 1, two; grade 2, two | No grade 3 or 4 local or systemic events | Local pain (n = 3), infection (n = 1), itching (n = 3), burning (n = 1), desquamation (n = 3), flu-like symptoms | NA |
| Plesnicar et al | 1982 | ILT + RT | NA | NA | NA | Marked erythema, ulceration, crusting, short flu-like syndrome | NA |
| Lai et al | 2003 | TT + RT | CTC v2.0, 1999 | Grade 1, 11; grade 2, eight; grade 3, two | Two of seven had grade 3 acute radiation dermatitis | Nausea, anorexia, acute/chronic radiation dermatitis, fatigue | All grade 3 toxicity resolved 2 to 3 weeks post-radiotherapy |
| Green et al | 2007 | TT + ILT | Simply said “Grade 3” | NA | One patient had rigors | Erythema, discharge, mild influenza like symptoms, rigors (n = 1), local infections (n = 2), nausea/dyspepsia (n = 2) | Most symptoms resolved within the first “few weeks” |
| Li et al | 2010 | TT + PDT | NCI CTC v3.0, 2009 | NA | Grade 3 occurred in 25% of patients (fatigue, pain requiring narcotics, dyspnea, cellulitis) | Rash (90%), pruritus (82%), pain (55%), fatigue (55%), anorexia (55%), nausea (36%), weight loss (36%), fever (18%), chills (9%), vomiting (9%), cellulitis (9%) | NA |
Abbreviations: CALGB, Cancer and Leukemia Group B; CTC, Common Toxicity Criteria; CTCAE, Common Terminology Criteria for Adverse Events; DIC, disseminated intravascular coagulation; ECT, electrochemotherapy; ILT, intralesional therapy; LFT, liver function test; NA, not available; NCI, National Cancer Institute; NIH, National Institutes of Health; PDT, photodynamic therapy; RT, radiotherapy; TT, topical therapy.
*
Systemic therapy allowed.
†
Toxicity grading scale from Overgaard J: Cancer 48:1116-1123, 1981.
‡
Study split up by drug used for ILT injections.
§
Study split by histology if toxicity information was extractable by histology.