Comparative Effectiveness of Surveillance, Primary Chemotherapy, Radiotherapy and Retroperitoneal Lymph Node Dissection for the Management of Early Stage Testicular Germ Cell Tumors: A Systematic Review
2020; Lippincott Williams & Wilkins; Volume: 205; Issue: 2 Linguagem: Inglês
10.1097/ju.0000000000001364
ISSN1527-3792
AutoresPhillip M. Pierorazio, Joseph Cheaib, Hiten D. Patel, Mohit Gupta, Ritu Sharma, Allen Zhang, Giorgia Tema, Eric B Bass,
Tópico(s)Sperm and Testicular Function
ResumoYou have accessJournal of UrologyReview Articles1 Feb 2021Comparative Effectiveness of Surveillance, Primary Chemotherapy, Radiotherapy and Retroperitoneal Lymph Node Dissection for the Management of Early Stage Testicular Germ Cell Tumors: A Systematic Review Phillip M. Pierorazio, Joseph G. Cheaib, Hiten D. Patel, Mohit Gupta, Ritu Sharma, Allen Zhang, Giorgia Tema, and Eric B. Bass Phillip M. PierorazioPhillip M. Pierorazio *Correspondence: James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, 600 N. Wolfe St./Park 217, Baltimore, Maryland 21287 telephone: 410-502-5984; FAX: 410-502-7711; E-mail Address: [email protected] Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author , Joseph G. CheaibJoseph G. Cheaib Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author , Hiten D. PatelHiten D. Patel Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland More articles by this author , Mohit GuptaMohit Gupta Department of Urology, New York University School of Medicine, New York City, New York More articles by this author , Ritu SharmaRitu Sharma The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author , Allen ZhangAllen Zhang The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author , Giorgia TemaGiorgia Tema Department of Urology, Sant'Andrea Hospital–“La Sapienza” University of Rome, Rome, Italy More articles by this author , and Eric B. BassEric B. Bass The Johns Hopkins Evidence-Based Practice Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001364AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: Cancer specific survival for men with early stage (I to IIB) testicular germ cell tumors is greater than 90% with any management strategy. The data regarding the comparative effectiveness of surveillance, primary chemotherapy, radiotherapy and retroperitoneal lymph node dissection were synthesized with a focus on oncologic outcomes, patient reported outcomes, and short and long-term toxicities. Materials and Methods: PubMed®, Embase® and the Cochrane Central Register of Controlled Trials were searched from 1980 to 2018 for studies addressing the effectiveness of surveillance, chemotherapy, radiotherapy and retroperitoneal lymph node dissection, according to pathology and clinical stage, for men with an early stage testicular germ cell tumor. Results: Cancer specific survival ranged from 94% to 100% for patients with early stage testicular germ cell tumors regardless of tumor histology and initial management strategy. For men with seminoma the median cancer specific survival was 99.7% (range 97% to 100%), 99.5% (96.8% to 100%) and 100% (100% to 100%) among those managed by surveillance, radiotherapy and chemotherapy, respectively. Median cancer specific survival for men with nonseminomatous testicular germ cell tumors was 100% (range 98.6% to 100%), 100% (96.9% to 100%) and 100% (94% to 100%) when managed by surveillance, retroperitoneal lymph node dissection and chemotherapy, respectively. Recurrence rates and toxicities varied by management strategy. For men with seminoma surveillance, chemotherapy and radiotherapy were associated with median recurrence rates of 15%, 2% and 3.7%, respectively. For men with nonseminomatous testicular germ cell tumors the median recurrence rates were 20.5%, 3.3% and 11.1% for surveillance, chemotherapy and retroperitoneal lymph node dissection, respectively. Surveillance was associated with minimal toxicities compared to other approaches. Primary chemotherapy had the highest rate of short-term toxicities and was associated with long-term risks of metabolic syndrome, hypogonadism, renal impairment, neuropathy, infertility and secondary malignancies. Toxicities with radiotherapy included acute dermatitis and long-term gastrointestinal complications, infertility and high rates of secondary malignancies (2% to 3%). Patients undergoing retroperitoneal lymph node dissection had significant risk of toxicity perioperatively and long-term infertility in men with anejaculation. Transient detriments in patient reported outcomes and quality of life were noted with all management options. Conclusions: Men with early stage testicular germ cell tumors experience excellent cancer specific survival regardless of management strategy. Management options, however, differ in terms of associated recurrence rates, short and long-term toxicities, and patient reported outcomes. The profile for each approach should be clearly communicated to patients and matched with patient preferences to offer the best individual outcome. Abbreviations and Acronyms AUA American Urological Association BEP bleomycin, etoposide and cisplatin CS clinical stage CVB cisplatin, vinblastine and bleomycin GCT germ cell tumor NSGCT nonseminomatous germ cell tumor QLQ-30 Quality of Life Questionnaire QOL quality of life RCT randomized controlled trial RPLND retroperitoneal lymph node dissection TGCT testicular germ cell tumor Testicular germ cell tumors affect approximately 9,000 men per year in the United States and approximately 50,000 men worldwide annually.1 The majority of men with testicular germ cell tumors present with stage I or II disease, most of whom are cured of cancer.2 The cancer specific survival approaches 100% for men with clinical stage I testicular germ cell tumors and is greater than 90% for men with clinical stage II disease.3 Men with advanced and metastatic testicular germ cell tumors (stage IIC or III) have a 5-year cancer specific survival of approximately 75% and typically require platinum based chemotherapy as a single or multimodality treatment plan for cure. For men with early stage (I to IIB) testicular germ cell tumors a variety of management options exist to achieve cure, including surveillance, primary chemotherapy, radiotherapy (for seminoma) and retroperitoneal lymph node dissection. While each management option offers excellent overall and cancer specific survival outcomes, variations exist in recurrence rates, short and long-term toxicities, and patient reported outcomes and quality of life. This systematic review was designed to synthesize evidence regarding the comparative effectiveness of stage specific management outcomes for men with early stage (I to IIB) TGCT in support of the AUA guideline on diagnosis and management of early stage testicular cancer. Outcomes for men with seminoma or nonseminomatous germ cell tumor were evaluated with a focus on oncologic outcomes, short and long-term toxicities, and patient reported outcomes. Materials and Methods The methods for this systematic review followed the Agency for Healthcare Research and Quality methods guide for effectiveness and comparative effectiveness reviews.4 Key questions were defined by the AUA guidelines panel for testicular cancer. This review, which serves as an executive summary of a comprehensive evidence report (supplementary Appendix 1, https://www.jurology.com), focuses on the following key question related to management strategies: What is the effectiveness and comparative effectiveness of surveillance, RPLND, chemotherapy and radiation according to pathology and clinical stage for men with an early stage TGCT? Study Selection PubMed, Embase and the Cochrane Central Register of Controlled Trials were used to search for studies from January 1980 to August 2018. Study selection was based on predefined eligibility criteria within a PICOT (Population, Intervention, Comparison, Outcome, Type) format (supplementary Appendix 2, https://www.jurology.com). Two reviewers independently screened titles, abstracts and full text for inclusion. Differences between investigators were resolved through consensus adjudication. DistillerSR (Evidence Partners, Ottawa, Ontario, Canada) was used to manage the screening process. Additional exclusion criteria were applied at the full text stage, and studies were restricted to publications since 1990. Data Extraction and Statistical Methods Standardized forms for data extraction were created and pilot tested prior to data extraction. Data abstraction was completed using forms created in Microsoft® Office Excel®. Reviewers extracted information on the general study characteristics, clinical data, pathological data including histology (seminoma and NSGCT), outcome measures and the results of each outcome (oncologic outcomes, short-term toxicities, patient reported outcomes, quality of life and long-term toxicities). One reviewer completed data abstraction, and the second reviewer confirmed the first reviewer’s data abstraction for completeness and accuracy. Risk of Bias Assessment and Strength of the Body of Evidence Two reviewers independently assessed the risk of bias in included studies. The Cochrane Collaboration’s tool for assessing the risk of bias was used for randomized controlled trials. For nonrandomized studies of treatment interventions ACROBAT-NRSI (Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions) was used.5 For noncomparative, single arm studies, 3 items were considered: design, consecutive enrollment and objective measurement of outcome. If all 3 items were rated favorably, the study was considered high quality; if just 1 item was unfavorable or unclear, the study was considered moderate quality. If 2 or 3 items were unfavorable or unclear, the study was considered low quality. Strength of evidence was rated by adapting the AUA’s 3 predefined levels of strength of evidence (supplementary Appendix 3, https://www.jurology.com). Results A total of 7,366 titles were screened. Of these 1,424 articles underwent full text review, and 80 studies reported in 82 articles were included (fig. 1 and supplementary table 1, https://www.jurology.com). Figure 1. Detailed summary of literature search Oncologic Outcomes and Second Primary Germ Cell Tumors Study Characteristics A total of 41 studies reported in 42 articles described oncologic outcomes data (supplementary table 2, https://www.jurology.com). Eight RCTs reported in 9 articles were included for the outcomes of relapse and overall survival.6–14 Two comparative studies (each with 500 patients or more) included oncologic outcomes for NSGCT15,16 and 12 for seminoma.17–28 Eight comparative studies (with less than 500 patients) reported oncologic outcomes for NSGCT29–36 and 3 for seminoma.37–39 Five of 8 uncontrolled studies (each with more than 1,000 patients) included oncologic outcomes for NSGCT and 7 for seminoma.40–47 A total of 12 studies were identified reporting rates of diagnosis of second primary TGCT for early stage seminoma or NSGCT.10,11,14,16,37,48–54 For oncologic outcomes the risk of bias was determined to be high for 23 studies and low for 18 studies; for data on second primary TGCT the risk of bias was high for 7 studies and low for 5 studies. Sources of bias included patient selection and measurement of disease recurrence. The strength of evidence for oncologic outcomes, including risk of second primary TGCT, was grade B. While cancer specific survival outcomes in randomized trials, comparative data and uncontrolled studies were consistently high, heterogeneity of data, study design and variation in reported recurrence rates prevented assignment of a higher strength of evidence. Seminoma Overall survival and cancer specific survival ranged from 90.3% to 100% and 96.8% to 100%, respectively, for men with early stage seminoma regardless of initial management strategy (table 1). Recurrence rates varied based on initial management strategy, tumor risk factors and duration of followup. For men with CS I seminoma calculated 5-year recurrence rates were 14% (range 6% to 27%) for surveillance, 3% (0% to 6%) for primary chemotherapy and 3% (1% to 5%) for radiotherapy (fig. 2, A). Risk adapted approaches identified groups of men at higher risk for recurrence; for men with CS I seminoma in risk adapted programs tumor diameter greater than 3 or 4 cm and rete testis invasion were risk factors for recurrence. Table 1. Median overall and cancer specific survival and relapse rates and followup for early stage testicular germ cell tumors (clinical stage I and II) by histology, management and study design Management Overall Survival Cancer Specific Survival Relapse Seminoma: Surveillance: Overall 97% (91.6%–100%), 61 mos (34–180) 99.7% (97%–100%), 60.5 mos (34–180) 15% (6.7%–26.9%), 60.5 mos (24–180) RCT Not reported Not reported Not reported Comparative 97% (92.2%–100%), 61 mos (34–120) 99.7% (97–100%), 60.5 mos (34–120) 12.7% (6.7–26.9%), 60 mos (24–127.2) Uncontrolled 95.8% (91.6–99.9%), 116 mos (52–180) 99.7% (99.3–100%), 120 mos (60–180) 17.4% (12.9–19.4%), 88.4 mos (52–180) Radiotherapy: Overall 98% (90.3–100%), 60 mos (51–152.4) 99.5% (96.8–100%), 60 mos (51–120) 3.7% (0.8–10.3%), 73.2 mos (36–144) RCT 99.4% (99.2–99.6%), 61 mos (60–61) 99.8% (99.3–100%), 60 mos (54–84) 4% (3.1–4.9%), 84 mos (60–144) Comparative 98.4% (94.8–100%), 60 mos (51–120) 99.4% (98.7–100%), 60 mos (51–120) 3.1% (0.8–10.3%), 64.2 mos (36–127.2) Uncontrolled 93.9% (90.3–97.5%), 89 mos (89–152.4) 99.4% (96.8–99.5%), 89 mos (89–89) Not reported Chemotherapy: Overall 99.2% (91.2–100%), 60 mos (24–120) 100% (100–100%), 60 mos (24–120) 2% (0–5.8%), 37.4 mos (24–64.8) RCT 99.7%, 60 mos 100%, 60 mos 5.3%, 60 mos Comparative 99.1% (91.2–100%), 60 mos (24–120) 100% (100–100%), 60 mos (24–120) 1.9% (0–5.8%), 34 mos (24–64.8) Uncontrolled Not reported Not reported Not reported NSGCT: Surveillance: Overall 99.7% (94.5–100%), 63 mos (24–180) 100% (98.6–100%), 64 mos (24–180) 20.5% (9.3–31.7%), 65.1 mos (24–180) RCT 100% (98.7–100%), 24 mos (24–64) 100% (100–100%), 24 mos (24–64) 19.8% (15–29.9%), 24 mos (24–64) Comparative 100% (97–100%), 66.2 mos (60–149) 99.5% (98.6–100%), 79.1 mos (40–149) 19.8% (9.3–25.6%), 92 mos (40–121.2) Uncontrolled 97% (94.5–99.4%), 121 mos (62–180) 99.3% (99.1–99.4%), 121 mos (62–180) 29.2% (18.7–31.7%), 121 mos (60.6–180) RPLND: Overall 100% (93.9–100%), 60 mos (18–92) 100% (96.9–100%), 60.6 mos (56–92) 11.1% (0–50%), 61.2 mos (56.4–92) RCT 93.9%, 61.2 mos 98.5% (96.9–100%), 58.6 mos (56–61.2) 29% (7.9–50%), 58.8 mos (56.4–61.2) Comparative 100% (97.1–100%), 59 mos (18–92) 100% (99–100%), 63 mos (58–92) 11.1% (0–11.8%), 65.9 mos (58–92) Uncontrolled Not reported Not reported Not reported Chemotherapy: Overall 99.5% (92–100%), 86.5 mos (60–149) 100% (94–100%), 81 mos (40–149) 3.3% (0.9–11%), 68.7 mos (36–122) RCT Not reported 100%, 56 mos 1.1%, 56 mos Comparative 99.5% (92–100%), 86.5 mos (60–149) 100% (94–100%), 86.5 mos (40–149) 4.8% (0.9–11%), 81 mos (36–122) Uncontrolled Not reported Not reported Not reported RPLND+chemotherapy: Overall 97.9%, 61.2 mos 99% (99–99%), 72 mos (61.2–82.8) 7.1% (6.8–7.5%), 58.6 mos (36–82.8) RCT 97.9%, 61.2 mos 99%, 61.2 mos 7.4% (7.2–7.5%), 58.6 mos (56–61.2) Comparative Not reported 99%, 82.8 mos 6.9% (6.8–6.9%), 59.4 mos (36–82.8) Uncontrolled Not reported Not reported Not reported Figure 2. Recurrence rates by management and study design. A, clinical stage I seminoma. B, clinical stage I NSGCT. Smallest icons represent rates from uncontrolled studies, medium sized icons are for comparative studies and largest icons are for randomized controlled trials. Lines of best fit are simple representations of general trend and are not weighted according to study design or sample size. Randomized trials of radiotherapy for CS I seminoma indicated similar rates of recurrence for men receiving 20 Gy or 30 Gy of para-aortic and dogleg radiotherapy. CS IIA and IIB seminomas were effectively treated with radiotherapy or chemotherapy without a clear recurrence or survival advantage to either therapy. Nonseminomatous Germ Cell Tumors Overall survival and cancer specific survival ranged from 92% to 100% and 94% to 100%, respectively, for men with early stage NSGCT regardless of initial management strategy (table 1). Different management strategies were associated with varying rates of recurrence. For men with CS I NSGCT calculated 5-year recurrence rates were 20% (range 10% to 35%) for surveillance, 4% (range 1% to 10%) for primary chemotherapy and 7% (range 0% to 12%) for primary RPLND not treated with adjuvant chemotherapy (fig. 2, B). Risk adapted programs for patients with CS I NSGCT identified lymphovascular invasion at pathological analysis of the testicular tumor as a risk factor for recurrence. Recurrence rates were similar for men with low volume CS II NSGCT undergoing primary RPLND or chemotherapy. After primary RPLND adjuvant chemotherapy reduced the risk of recurrence in men with pathological stage II NSGCT (table 1). Late Recurrences and Second Primary Germ Cell Tumors Late relapse of TGCT is defined as disease recurrence more than 2 years after completion of primary treatment. Late recurrences were reported beyond a decade from initial diagnosis in all management strategies but were most commonly reported after surveillance. Second primary TGCTs were reported overall in 1.1% of men (56 of 4,914) over a followup period of 29 to 156 months (median 60). There was no distinguishable difference in risk of second primary TGCT based on initial tumor histology, stage or treatment received. Short-Term Toxicities and Patient Reported Outcomes Study Characteristics A total of 41 studies reported in 42 articles contained data on short-term toxicities (supplementary Appendix 4, https://www.jurology.com). Three were RCTs (reported in 4 articles), 11 were comparative and the remainder were single arm studies. A total of 17 studies included men with seminoma and 24 included men with NSGCT. For men with seminoma 2 studies compared more than 1 management strategy,37,38 while 1 study evaluated chemotherapy alone.55 The remaining 14 studies evaluated radiotherapy.10,11,50,53,54,56–64 For men with NSGCT a single RCT of RPLND vs chemotherapy was included.6,65 Two comparative studies evaluated surveillance and RPLND.29,36 Three studies compared outcomes for men undergoing surveillance and chemotherapy.16,34,66 One study evaluated RPLND and chemotherapy,30 and 1 evaluated surveillance, RPLND and chemotherapy.33 Three single arm studies evaluated chemotherapy.49,67,68 Nine studies reported outcomes for open RPLND,64,69–76 and 3 reported outcomes for laparoscopic RPLND.77–79 Finally, 1 study compared open and laparoscopic RPLND.32 Patient reported outcomes including QOL were reported in 12 of the 41 studies (supplementary Appendix 4, https://www.jurology.com).10,11,30,32,37,55,58,60,63–65,68 The RCT of RPLND vs chemotherapy for men with early stage NSGCT provided patient reported outcomes in a followup study.6,65 Two RCTs of different radiotherapy regimens for early stage seminoma also presented patient reported outcomes.10,11 Comparative studies included a study reporting comparative outcomes for men with stage II NSGCT undergoing RPLND or chemotherapy,30 and a study evaluating surveillance, chemotherapy and radiotherapy for men with early stage seminoma.37 One uncontrolled study reported outcomes for chemotherapy55 and 4 included patient reported outcomes in men undergoing radiotherapy.58,60,63,64 Five studies reported outcomes using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire.30,32,60,65,68 When available, data from studies were combined and are reported below. The risk of bias was determined to be high for 38 studies and unclear for 3. Sources of bias included patient selection, lack of randomized studies and lack of objective outcome measurement. The strength of evidence for short-term toxicities and patient reported outcomes was grade C due to heterogeneity of data and lack of standardized toxicity reporting. Short-Term Toxicities Short-term toxicities varied by management strategy, and in general most therapies were well tolerated with low rates of serious toxicities (table 2). Very few patients died during treatment of early stage TGCT regardless of treatment strategy. Table 2. Short-term toxicities by treatment Toxicity Surveillance Radiotherapy Chemotherapy RPLND Any toxicity Sickness—6%, diarrhea—4%, indigestion—11%37 Not reported Cumulative toxicities—80%–95% of men receiving 1 or 2 cycles of BEP or CVB for NSGCT,34,66 grade 3 and 4 toxicities—37.4% and 2.3%, respectively, of men with NSGCT receiving 1 cycle of BEP6 Total complications—3%–39.1% (mean 16%),6,36,69-72,75,79 minor complications—0%–42% (mean 18.5%)6,36,69-72,75,79 major complications—0%–26.1% (mean 8.7%)6,36,69-72,75,79 Death Not reported 1 of 27056 2 of 78,30 1 of 11449 1 of 15770 Auditory toxicity Not reported Difficulty hearing before—12%, difficulty hearing after—15%63 Acute tinnitus—8% of men receiving 2 cycles of BEP49 Not reported Dermatologic toxicities Not reported Acute dermatitis—6%–19% (mean 11%), late dermatosis, subcutaneous fibrosis and skin changes—0%–19% (mean 3.5%)10,57,62,63 Low grade alopecia—5.4%–56.3% of men receiving 2–4 cycles of chemotherapy (mean 31%),6,30,67,68 high grade alopecia—0%–58.1% (mean 17%); dermatitis—0%–4.6%, no grade 4 toxicities; stomatitis—1%–19% (mean 5.7%), no grade 4 toxicities6,30,67,68 Low grade alopecia—8.5%–42.7% of men undergoing RPLND with adjuvant chemotherapy (mean 21.7%), high grade alopecia—0%–46.3% of men undergoing RPLND with adjuvant chemotherapy (mean 12%); dermatitis—0%–1.7% of men; stomatitis—1.1%–9.6% of men; keloid—0.7%–10% of men undergoing open RPLND, 0% of men undergoing laparoscopic RPLND6,29,30,32,69 Gastrointestinal toxicities Not reported Mild nausea and/or vomiting—8%–62% (mean 33%), moderate or severe nausea and/or vomiting—0%–19% (mean 5%); mild diarrhea and late bowel irritation—0%–28% (mean 6%), moderate to severe diarrhea and late bowel irritation—0%;10,11,37,50,53,54,57,58,60-62,64 peptic ulcer disease—2 cases (in pts with antecedent history)53,61 Decreased appetite—80% of men receiving 3–4 cycles of BEP;30 obstructive symptoms—0%–27% of men (mean 4%), 27% of men with grade 3–4 constipation receiving 1–2 cycles of CVB in 1 study;34 diarrhea—0%–17.6% of men (mean 4%), most commonly grade 1 toxicity; nausea/vomiting—0%–71% of men (mean 17.6%), low grade toxicities (grade 1–2)—1.4%–71% (mean 28.8%);6,30,34,37,38,49,55,66-68 late indigestion—24% of men in 1study37 Decreased appetite—87% of men, low grade toxicities—72%;30 bowel obstruction, ileus, constipation and obstipation—0%–20% (mean 2.9%), major small bowel obstruction—0.4%–2.0%; low grade diarrhea—3.2%–10.6%, high grade diarrhea—none reported; low grade nausea—3.1%–15% of men, high grade diarrhea—none reported; vomiting—0%–31.9% (mean 12.5%) of men undergoing RPLND, low grade—9.2%–31.9% (mean 24%)6,29,30,32,36,64,69-73,75,78 Genitourinary toxicities Not reported Acute bladder toxicity—none, late bladder toxicity—0%–4% (mean 1%);54,57,58,62 erectile dysfunction—17%58 Anejaculation—15.6% of men receiving 3–4 cycles of BEP30 Antegrade ejaculation—0%–100% of men undergoing RPLND (mean 73%), 24%–100% (mean 81%) when nonnerve sparing techniques were excluded; urinary tract injuries—0%–2.8% (mean 0.9%); urinary tract infections—0.2%–1.0% of men undergoing RPLND (mean 0.6%)29,30,32,36,69-71,73-76,78,79 Hematologic toxicities Not reported Low grade leukopenia—2%–29% (mean 11%), high grade leukopenia—0%–1%; thrombocytopenia—0%–0.7%10,11,53,61 Low grade anemia—0%–64.4% (mean 24%), high grade anemia—0%–2.5% (mean 0.8%); low grade neutropenia/leukopenia—4.3%–37.3% (mean 16.5%),6,29,30,34,38,49,55,66-68 high grade neutropenia/leukopenia—60% (mean 10.3%); neutropenic fever—0%–2.3%, neutropenic infection—25% of men in 1 study;34 low grade thrombocytopenia—0%–16% (mean 6%), high grade thrombocytopenia—0%–18.4% (mean 3.6%); low grade bleeding—1.4%–4.1%; deep venous thrombosis and pulmonary embolus—0%–1.1% of men;6,29,30,34,38,49,55,66-68 late hematological toxicities—none reported Low grade anemia—6.9%–22.2% (mean 16%), high grade anemia—0%–6.9% (mean 2.4%); bleeding—0%–18.4% of pts in operative or perioperative setting (mean 2.1%); hematoma—0%–6% (mean 1.2%); deep venous thrombosis and pulmonary emboli—0%–0.9% (mean 0.5%);6,29,30,32,69-73,75,79 leukopenia—1.2%–26.9% of men receiving adjuvant chemotherapy (mean 16.2%);6,30 thrombocytopenia—0%–16% of men receiving adjuvant chemotherapy (mean 6.1%)6,30 Infectious (and wound related) toxicities Not reported Not reported 0%–10.9% (mean 2.6%) with no grade 4 toxicities,30,66,67 chemotherapy alone—none reported Systemic infections—0%–24% (mean 3.1%), wound infections—0%–10% of men undergoing RPLND (mean 3%), ventral (or other) hernia—0%–6% (mean 1.3%)6,30,32,36,69-73,75 Lymphatic toxicities Not reported Not reported Not reported Lymphocele and lymphedema—0%–13.2% (mean 1.9%), chylous ascites and hydrothorax—0%–12.2% (mean 1.5%)6,29,30,69-73,75,78,79 Neurologic toxicities Not reported 0%–0.8%63 Neuropathy, neurotoxicity and parasthesias—0%–41% (mean 5.8%) of men, low grade (most common)—1.4%–41% (mean 14%) 6,30,34,49,66,68 Acute neuropathy and parasthesias—0%–8.5% of men undergoing RPLND (mean 1.4%)6,30,70,79 Pulmonary toxicities Not reported 4% of pts in 1 study60 Low grade acute pulmonary toxicity—4%–12.2% of men (mean 7%),30,34,49,66,68 high grade—none reported; late pulmonary toxicity—6.8% of men in 1 study30 Pneumonia, atelectasis and pleural effusion—0%–7.2% of men undergoing RPLND (mean 2.4%)30,32,69-73,75 Renal toxicities Not reported Not reported Grade 1 renal toxicity—0.7%–3% of men, grade 2 renal toxicity—0% of men, grade 3 renal toxicity—0%–1% of men, grade 4 renal toxicity—0% of men30,34,49,55,66,68 0%–4.0% of men undergoing RPLND (mean 1%)6,30,75 Dose related toxicities Not reported Not reported 1 study reported minimal difference in men receiving 1–2 courses of CVB34 Not reported Other surgical complications Not reported Not reported Not reported Laparoscopic RPLND converted to open—0%–5.1% of men undergoing RPLND (mean 2%), vascular injuries (related to great vessel or lumbar anatomy)—1.5%–3.9%, ureteral injuries—0%–5%, renal artery laceration—0%–0.7%30,32,69,71,73,77-79 Radiotherapy was associated with higher rates of acute dermatitis than other management strategies. Gastrointestinal complications occurred in up to 60% of patients (mean 33%); however, most toxicities were mild and included nausea, vomiting and diarrhea. Exacerbation of peptic ulcer disease may be significant in men with an antecedent history. Dermatological and gastrointestinal toxicities may be dose related and lower in men receiving doses less than 30 Gy compared to men receiving doses more than 30 Gy. Primary chemotherapy had the highest rate of short-term toxicities, reported in up to 80% to 95% of men. Most toxicities were mild and self-limited. Unique toxicities to chemotherapy included acute tinnitus, alopecia, neuropathy, and pulmonary and renal toxicities. Rates of gastrointestinal and hematological toxicities were highest in men undergoing primary chemotherapy. RPLND had moderate rates of short-term toxicities, typically reported in the perioperative period. Unique toxicities associated with RPLND included anejaculation, lymphatic leaks (chylous ascites, lymphedema), surgical injuries (most commonly vascular injuries and urinary tract injuries) and surgical infections (wound, pulmonary). Rates of gastrointestinal toxicity were moderate and included obstructive symptoms (bowel obstruction, ileus, constipation and obstipation) rather than the nausea, vomiting and diarrhea associated with radioth
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