Multidisciplinary approach to muscle-invasive bladder cancer is imperative to achieve optimal long-term cancer control. Radical cystectomy, pelvic lymph node dissection, and urinary diversion have been the mainstay of therapy for decades. Laparoscopic and robotic-assisted surgical techniques are becoming increasingly prevalent, and have shown short-term benefits in terms of blood loss, less pain, and smaller incisions. Neoadjuvant chemotherapy plus surgery results in absolute survival advantage and this approach is encouraged in appropriate patients. A similar survival advantage with the use of adjuvant chemotherapy has yet to be convincingly demonstrated. Bladder-preservation protocols involving a visibly complete transurethral resection followed by chemoradiation may be a feasible option for select patients.
Key points
- •
Surgeon-controlled variables including negative surgical margins and extended lymph node dissection are essential to achieve optimal outcomes for patients treated by radical cystectomy.
- •
Neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin significantly improves the survival of patients undergoing radical cystectomy and represents the optimal treatment approach for patients with muscle-invasive bladder cancer. The use of carboplatin-based regimens is not recommended.
- •
In addition to insufficient evidence for use of adjuvant chemotherapy, its use and tolerability may be compromised after major surgery because of surgical complications.
- •
In select patients, bladder-preservation protocols may result in acceptable survival and low toxicity rates, although it has not been widely embraced in the genitourinary oncology community.
Introduction
Optimal management of invasive bladder cancer involves a multidisciplinary therapeutic approach for improved disease-free and overall survival. Approximately 30% of patients present with muscle-invasive bladder cancer at diagnosis. A total of 50% to 70% of those with high-grade, non–muscle-invasive disease recur and up to 50% progress to muscle-invasive disease. If left untreated, 85% of patients with muscle-invasive bladder cancer die of disease within 2 years of diagnosis. Because of high morbidity and mortality of muscle-invasive bladder cancer, single therapeutic modality may not provide optimal cancer control.
Radical cystectomy plays a pivotal role in the care of patients with invasive bladder cancer and has been the mainstay of treatment for decades. Overall survival for patients with muscle-invasive bladder cancer treated by radical cystectomy ranges from 50% to 60%. Per stage, survival for pT0-2 N0, pT3-4 N0, and pTany N1-3 is 70% to 80%, 45% to 55%, and 25% to 35%, respectively. Despite significant advances in the understanding and management of bladder cancer, outcomes have largely remained unchanged in the last 30 years. Bladder-preservation strategies involving a visibly complete transurethral bladder tumor resection followed by radiation therapy and chemotherapy may achieve similar survival rates in select patients. This article reviews different treatment options and discusses possible management strategies to improve outcomes.
Introduction
Optimal management of invasive bladder cancer involves a multidisciplinary therapeutic approach for improved disease-free and overall survival. Approximately 30% of patients present with muscle-invasive bladder cancer at diagnosis. A total of 50% to 70% of those with high-grade, non–muscle-invasive disease recur and up to 50% progress to muscle-invasive disease. If left untreated, 85% of patients with muscle-invasive bladder cancer die of disease within 2 years of diagnosis. Because of high morbidity and mortality of muscle-invasive bladder cancer, single therapeutic modality may not provide optimal cancer control.
Radical cystectomy plays a pivotal role in the care of patients with invasive bladder cancer and has been the mainstay of treatment for decades. Overall survival for patients with muscle-invasive bladder cancer treated by radical cystectomy ranges from 50% to 60%. Per stage, survival for pT0-2 N0, pT3-4 N0, and pTany N1-3 is 70% to 80%, 45% to 55%, and 25% to 35%, respectively. Despite significant advances in the understanding and management of bladder cancer, outcomes have largely remained unchanged in the last 30 years. Bladder-preservation strategies involving a visibly complete transurethral bladder tumor resection followed by radiation therapy and chemotherapy may achieve similar survival rates in select patients. This article reviews different treatment options and discusses possible management strategies to improve outcomes.
Surgical issues
Quality of Radical Cystectomy
Radical cystectomy is a critical component in the treatment of invasive bladder cancer. Suboptimal surgery dramatically decreases overall survival. Modifiable surgical factors that can significantly improve survival include surgical margin status and number of lymph nodes removed. Analysis of the SWOG 8710 trial showed that positive margins and removal of fewer than 10 nodes were associated with significantly poorer outcomes. The adjusted hazard ratio for death of patients with positive versus negative surgical margin was 2.7 (95% confidence interval, 1.4–2.8). When compared with negative-margin group, local recurrence was 11.2 times greater in the positive-margin group. In a recent paper by Mitra and colleagues, a review of 447 patients showed that positive surgical margin status was significantly associated with worse postrecurrence overall survival.
Number of lymph nodes removed and overall survival have a linear correlation with continuous rise in survival with increasing number of lymph nodes removed. Herr and colleagues showed that disease-specific survival was greater for patients with more than 14 nodes removed as compared with removal of 9 to 14 nodes and 1 to 8 nodes. The quality of surgery may be improved by striving for negative surgical margins and removing adequate number of lymph nodes at the time of surgery.
Another factor that may influence outcomes is surgeon training. In the analysis of the SWOG 8710 study, 106 surgeons were included from 1987 to 1998, of which 38% were fellowship-trained urologic oncologists. No pelvic lymph node dissection (PLND) was done in 9% of the cases and in 50%, less than 10 nodes were removed. Positive surgical margin rate was 10% overall, but 4% for urologic oncologist and 16% for others. Local recurrence rate for urologic oncologist was 6% versus 23% for others. The type of surgeon (fellowship-trained vs others) was a significant predictor of number of nodes removed, local recurrence, and survival. The surgical volume among urologic oncologists does not play a significant role in terms of surgical outcomes. Sixteen surgeons from four centers of excellence with varying experience were compared. Seven surgeons had done fewer than 50 radical cystectomies, whereas four had done more than 100 procedures over a 3-year period. No significant difference was found among urologic oncologists with regards to number of lymph nodes removed and surgical margin status.
To summarize, positive margins are associated with increased local recurrence and worse survival. Surgery by a fellowship-trained urologic oncologist versus others is associated with greater number of nodes removed, lower local recurrence, and higher survival.
Standard Versus Extended PLND
Clinical staging for lymph nodes relies on imaging including computed tomography or magnetic resonance imaging; however, studies have shown that 19% to 28% of those who are N0 preoperatively on imaging are found to have positive nodal disease, emphasizing the importance of LND. Optimal extent of LND at the time of surgery that provides the best survival is widely debated. “Standard” lymphadenectomy is removal of all tissue within the boundaries of common iliac artery bifurcation where ureter crosses the vessels, internal iliac, external iliac, and obturator fossa. However, several studies suggest that this may not be sufficient to provide adequate cancer control. An “extended” LND is described as dissection up to the aortic bifurcation superiorly, genitofemoral nerve laterally, lymph node of Cloquet inferiorly, obturator fossa posteriorly, and presacral nodes. The concept of extended PLND (EPLND) has come about because of lymph node mapping studies that reveal the high positivity rate of lymph nodes above the bifurcation of the common iliac vessels. Among 336 patients, 19% had lymph node metastasis with 34.4% of those above the bifurcation of the common iliac vessels. In one study, 290 patients were evaluated for lymph node positivity rate in 12 different anatomic locations. The lymph node positivity in each location ranged from 2.9% to 14.1%. Common iliac and presacral nodal involvement was as common as distal nodes. Therefore, if dissection were limited to the obturator fossa, 74% of the positive lymph nodes would not be detected.
Similar results were found in another study of 176 patients undergoing radical cystectomy and PLND, where 24% of the patients were found to have lymph node involvement. The distribution of involved lymph nodes was as follows: 4% in aortic bifurcation, 13.7% in common iliac nodes, 5.1% in presacral nodes, 26% in pelvic nodes, 2.8% in perivesical nodes, and 5.7% in unspecified nodes. Additionally, LND is always bilateral because of bilateral lymph drainage. This is exemplified by a study that showed that 39% of patients with positive lymph nodes had bilateral involvement. Other series have also supported this finding.
EPLND has several clinical advantages because it allows for more accurate staging, removes occult metastases, and correlates to greater recurrence-free survival. It is of value even in those patients with clinically organ-confined, node-negative disease. In one study, 5-year recurrence-free survival was 90% in those who underwent EPLND versus 71% for standard PLND. Another study of 658 patients with N0M0 disease based on preoperative clinical staging also showed greater recurrence-free survival for EPLND. Among those with positive lymph nodes on pathology, patients who underwent limited LND had 7% 5-year recurrence-free survival compared with 35% for EPLND. For those with pT2N0 disease or node-negative disease, the 5-year recurrence-free survival was 67% for limited and 77% for EPLND, and for patients with pT3N0 disease, it was 23% and 57% ( P <.0001), respectively. EPLND improved survival in node-negative and node-positive invasive bladder cancer.
Morbidity rates of EPLND in contemporary series are comparable with standard LND. Although it may prolong operative time, there is no significant difference in perioperative mortality, early complications, need for blood transfusions, and lymphocele formation. Lymphocele and lymphedema rates were 2% for patients in whom less than 16 lymph nodes were removed and 1% where 16 or more lymph nodes were removed.
The number of lymph nodes involved is an important factor for survival. Recurrence-free and overall survival are directly related to the number of lymph nodes involved, with significantly decreased survival for those with five or more positive lymph nodes when compared with those with less than five positive lymph nodes. In a study by Herr, the 5-year overall survival was 38% for patients with less than five positive lymph nodes versus 18% for those with five or more positive lymph nodes.
The concept of lymph node density (LNDt) was designed to include not only the number of lymph nodes involved, but also take into account the extent of LND. LNDt greater than 20% correlates with worse disease-free survival. In a study of 1054 patients, Stein and colleagues showed that 10-year recurrence-free survival for patients with LNDt less than or equal to 20% was 43% versus 17% for LNDt greater than 20%. Similarly, another study of 133 patients showed that LNDt was among the most important factors in determining disease-specific survival after cystectomy. Five-year disease-specific survival for patients with LNDt less than or equal to 20% was 54%, whereas it was 0% for LNDt greater than 20%. A study by Herr of 162 patients with lymph node–positive bladder cancer showed 5-year disease-specific survival of 5% for LNDt greater than 20% and 60% for LNDt less than or equal to 20%. This study also compared the use of LNDt with TNM nodal status and showed that LNDt was a better prognostic indicator of recurrence and disease-specific survival. Another study from Memorial Sloan-Kettering Cancer center and M.D. Anderson Cancer Center confirmed this finding. The 5-year disease-specific survival of 134 patients was 55% for patients with LNDt less than or equal to 20% versus 15% for LNDt greater than 20%. Pathologic nodal status and LNDt were important markers of worse disease-specific survival, but in a multivariate model, only LNDt was significantly associated with decreased disease-specific survival.
To summarize:
- •
Rate of lymph node positivity in clinical negative nodes is approximately 25%.
- •
Lymph node mapping studies reveal that substantial number of lymph nodes is positive above the bifurcation of the common iliac vessels.
- •
EPLND improves local recurrence and survival as compared with standard LND in node-positive and node-negative invasive bladder cancer.
- •
Perioperative morbidity and mortality are similar for standard and EPLND.
- •
Involvement of greater than five lymph nodes is an indicator of lower recurrence-free and overall survival.
- •
LNDt greater than or equal to 20% correlates to improved disease-specific survival and may be a better marker of outcomes than number of positive lymph nodes.
Outcomes of Minimally Invasive Surgical Approaches
Minimally invasive surgery plays an increasingly important role in management of invasive bladder cancer. Theoretical benefits of minimally invasive surgery are decreased blood loss and transfusion rate because of better visualization and positive pressure from pneumoperitoneum, smaller incision and resulting improved pain control, decreased morbidity and mortality, better optics to allow aggressive nerve-sparing, higher potency and continence rates, and preservation or improvement in oncologic outcomes.
Recent studies show that some of the benefits of minimally invasive surgery may be improved analgesic requirements and reduced blood loss along with lower transfusion rates. It may also result in quicker recovery, shorter hospital stay, and fewer complications. These results have yet to be definitively proved. In terms of cancer control, surgical margin status and number of lymph nodes removed are similar in retrospective studies. A single-institution, small, prospective, randomized noninferiority trial was done to compare open versus robotic-assisted radical cystectomy. Robotic-assisted radical cystectomy resulted in significant reduction in estimated blood loss, time to flatus and bowel movement, and use of narcotic pain medication, while resulting in similar complication rate and hospital stay. Operative time was significantly higher in robotic-assisted surgery (4.2 vs 3.5 hours). Positive margin rate and lymph node yield was similar with both techniques. Based on these select studies, oncologic outcomes do not seem to be compromised by use of robotic assistance; however, longer follow-up is needed.
In summary, minimally invasive surgery results in improved pain control, reduced blood loss and transfusion rates, but operative time is higher. Surgical margin rates and extent of LND seem to be similar between minimally invasive and open surgical approaches. Long-term oncologic outcomes with minimally invasive surgery remain to be seen, although shorter-term outcomes do not seem to be compromised.
Chemotherapy
The main role of perioperative chemotherapy in clinically localized bladder cancer is to deliver effective systemic therapy while the burden of micrometastatic disease is minimal. Theoretically, this should lead to tumor downstaging (ie, pathologic complete response); delay in disease recurrence; and overall survival improvement. The controversy, however, is the timing of its administration (ie, preoperative vs postoperative).
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is standard of care for muscle-invasive bladder cancer. During the past two decades, a series of cisplatin-based regimens were evaluated in randomized trials, culminating in two large trials demonstrating a survival impact of chemotherapy administered in the neoadjuvant setting. A randomized, controlled trial (SWOG 8710) comparing three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus radical cystectomy versus cystectomy alone increased the survival from a median of 46 months in cystectomy-alone group to 77 months in the combination group. There was a 14% absolute improvement in overall survival at 5 years in the combination group. This was observed in all tumor stages, especially if there were complete pathologic response. Rate of pathologic T0 in patients receiving neoadjuvant chemotherapy is 33% to 40%, whereas it is 6% to 15% for those who undergo radical cystectomy alone.
Alternative treatment regimens have been investigated in several studies. A European Organization for Research and Treatment of Cancer trial randomized 976 patients to definitive local therapy or three cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV). This trial showed a 16% and 23% reduction in all-cause mortality and death or metastasis, respectively, for patients receiving neoadjuvant CMV versus those receiving local therapy alone. The 3-year survival and 10-year survival also increased from 50% to 56% and 30% to 36%, respectively, in the neoadjuvant chemotherapy group. A meta-analysis of 11 phase III randomized, controlled trials that included more than 2600 patients showed a 5% absolute improvement in survival conferred to those patients who received platinum-based neoadjuvant chemotherapy ( P = .016). The overall survival improvement observed was achieved irrespective of the type of local definitive treatment administered (surgery or radiation).
The use of cisplatin plus gemcitabine (GC) in the perioperative setting has not been prospectively evaluated. Small retrospective series have evaluated the toxicity profile of GC and its ability to lead to tumor down-staging. Four cycles of GC seem to lead to pT0 in 26% of the patients; these data mirror the rate of pT0 disease (28%) observed in the neoadjuvant MVAC trial. Albeit improved side effect profile is the argument often used in the community to favor GC over MVAC, to date no prospective data have compared MVAC with GC in the perioperative setting. Similar to GC, carboplatin-based chemotherapy has not been properly evaluated in the perioperative setting. Carboplatin is an inferior agent to cisplatin and should not be used in the neoadjuvant setting.
Advantages of neoadjuvant chemotherapy include better tolerability of systemic therapy, avoidance of potential delay in delivering systemic therapy while awaiting recovery from surgical treatment, prognostic benefit of monitoring response to chemotherapy, reduction of tumor volume, and treatment of micrometastatic disease. If chemotherapy is deferred until after radical cystectomy, an estimated 30% of the patients may not be able to get adjuvant chemotherapy because of prolonged postoperative convalescence, complications, or compromised renal function.
Despite demonstrable advantages, the use of neoadjuvant chemotherapy has been low. National Cancer Database shows that only 9% of the patients receive neoadjuvant chemotherapy, but the rate has increased from 6% in 2003 to 13% in 2007. A Canadian group revealed a 14% use rate for neoadjuvant chemotherapy after the publication of practice guidelines for muscle-invasive bladder cancer in 2005. Another study evaluated the use of neoadjuvant chemotherapy in a tertiary care center in the United States, and reported that only 17% of eligible patients were administered neoadjuvant chemotherapy.
Potential reasons for underuse of neoadjuvant chemotherapy include inaccurate clinical staging, delay in definitive surgery because of nonresponse, delay in delivery of chemotherapy or definitive local surgery, modest gain in overall survival, and toxicities of chemotherapy rendering patients with higher comorbidities unsuitable for surgery.
To summarize, neoadjuvant chemotherapy with MVAC results in better survival, and is associated with higher pathologic T0 stage. Carboplatin is inferior to cisplatin and should not be used in the neoadjuvant setting. CMV and GC are alternative chemotherapy regimens that have shown significant clinical response, but these regimens have not been compared with MVAC in head-to-head trials. Although neoadjuvant chemotherapy is clearly indicated in patients with muscle-invasive bladder cancer, the use rates are low.
Adjuvant Chemotherapy
Although adjuvant chemotherapy lacks strong evidence for its use, most American clinicians prefer to delay chemotherapy in fear of not being able to complete local definitive therapy, and to provide a perioperative benefit for a more well-defined population.
Arguments in favor of adjuvant chemotherapy are adequate pathologic staging allowing delivery of chemotherapy to only those patients who are at high risk of progression, and avoidance of overtreatment and delay in definitive surgical therapy. The trials for adjuvant chemotherapy, however, suffer from poor accrual, early study terminations, low power, variability in regimens, and lack of long-term follow-up ( Table 1 ).
| Author (Year) | No. of Patients | Trial Design | Survival Advantage |
|---|---|---|---|
| Skinner et al, 1991 | 91 | Cystectomy ± CISCA | Yes, OS |
| Stockle et al, 1995 | 49 | Cystectomy ± MVAC/MVEC | Yes, DFS only |
| Freiha, 1996 | 55 | Cystectomy ± CMV | No |
| Studer et al, 1994 | 77 | Cystectomy ± cisplatin | No |
| Cognetti et al, 2012 | 194 | Cystectomy ± GC | No |
| Stadler et al, 2011 | 114 | Cystectomy ± MVAC | No |
Some of the earlier trials comparing cystectomy plus cisplatin-based adjuvant chemotherapy showed mixed results, with two studies showing survival advantage. However, these trials were underpowered and inconclusive. Studies have been done to incorporate molecular markers to better stratify patients for adjuvant chemotherapy. A phase III trial randomized 114 patients with p53-positive status on cystectomy specimens to adjuvant MVAC versus observation. This trial failed to demonstrate a benefit when p53 status, a known molecular alteration in bladder cancer, was used as a prognostic indicator. This trial also failed to demonstrate an advantage of adjuvant chemotherapy in this p53-positive patient cohort.
A meta-analysis of all the randomized cisplatin-based adjuvant chemotherapy trials including 491 patients revealed a 25% relative risk reduction for all-cause mortality and 9% absolute survival advantage with adjuvant chemotherapy. It also showed a 32% relative increase in disease-free survival and 12% absolute improvement. However, because of poor quality of trials and small number of patients, the Advanced Bladder Cancer Collaboration concluded that there was insufficient evidence for its use. A large retrospective study of 932 patients from 11 institutions treated with adjuvant chemotherapy reported survival benefit for adjuvant chemotherapy, especially in higher-risk patients (≥T3 disease or nodal involvement).
Potential limitations for use of adjuvant chemotherapy are long recovery time after radical cystectomy, possibility of serious perioperative complications leading to difficulty in administering treatment, or decreased ability to tolerate treatment. Approximately 60% of patients have perioperative complications and 20% to 27% require readmission within 90 days of surgery, which hinders delivery of adjuvant chemotherapy in 30% of eligible patients. The data regarding neoadjuvant and adjuvant chemotherapy must be considered when making a decision regarding choice of appropriate regimen.
To summarize, meta-analysis of all randomized adjuvant chemotherapy trials revealed a 25% relative risk reduction for all-cause mortality and 9% absolute survival but more robust evidence is needed to make definitive recommendations. Because of perioperative complications, 30% of the patients eligible for adjuvant chemotherapy are unable to receive this treatment.
Chemoradiation therapy
Bladder Preservation
Although robust evidence exists in favor of neoadjuvant chemotherapy and radical cystectomy, some patients with low performance status and high baseline comorbidities may not be able to tolerate surgery. The trimodal approach to selective bladder preservation includes aggressive transurethral resection with goal of complete resection, followed by concomitant radiation and chemotherapy. Chemotherapy serves to radiosensitize the tumor and treats occult metastasis. After these treatments, a cystoscopy is repeated and those with persistent disease proceed to radical cystectomy.
Although no standardized inclusion or exclusion exists, the patients who may be candidates for this approach are those with solitary tumors less than 5 cm, absence of carcinoma in situ, resectable disease, absence of hydronephrosis, normal functioning bladder and bowel, willingness to comply with extensive follow-up schedule, or those who are unfit or unwilling to undergo surgery. Generally, accepted exclusion criteria include patients with multifocal tumors or large solitary tumor (>5 cm); unresectable disease or incomplete transurethral resection; prior pelvic radiotherapy; and presence of hydronephrosis or carcinoma in situ.
A multicenter, randomized, phase III trial of 360 patients with T2 to T4a bladder cancer compared radiotherapy alone with radiation and chemotherapy (mitomycin C and fluorouracil). The chemoradiation group had significantly higher locoregional disease-free survival relative to radiotherapy alone at a median follow-up of 70 months. Overall survival at 5-years was similar between the groups. Grade 3 or 4 adverse events were not significantly increased in the chemoradiation group, with preservation of long-term bladder function. Comparison of salvage cystectomy rate was underpowered, but it was 11.4% in the chemoradiation group and 16.8% in the radiotherapy-alone group ( P = .07).
Rates of disease-free and overall survival for bladder-preservation protocols have been reported in several studies, but studies directly comparing radical cystectomy with bladder preservation are sparse. Some of the earlier studies reported 3- to 5-year disease-free survival of 62% to 66%, and overall survival of 49% to 54%. One study revealed 10-year overall survival of 36%, which is similar to studies with radical cystectomy for muscle-invasive disease. One-third of the patients ultimately required salvage radical cystectomy for local recurrence, but none because of treatment-related toxicity. Muscle-invasive disease recurrence should prompt treatment with radical cystectomy. Management of non–muscle-invasive disease is controversial. In a study of 190 patients, 26% rate of non–muscle-invasive disease recurrence was noted. The 5- and 8-year survival rates were not significantly different between those with recurrence and those without recurrence. However, 8-year survival with a functional bladder was significantly lower in those with non–muscle-invasive recurrence (34%) compared with recurrence-free patients (61%).
Recent studies have investigated broader chemotherapeutic options including paclitaxel, cisplatin, and gemcitabine in combination with radiotherapy, and revealed 5-year disease-specific survival of 71% and overall survival of 56%. In this study of 80 patients, concomitant cisplatin and paclitaxel with hyperfractionated radiotherapy to 21 Gy were administered, and complete responders received adjuvant gemcitabine with cisplatin with radiotherapy to total 45 Gy. In another study, addition of gemcitabine to cisplatin resulted in 5-year disease-specific survival of 79% and overall survival of 70% at a median follow-up of 74 months.
Challenges with trimodal therapy include lack of standardized chemoradiation protocols, possible need for salvage cystectomy and associated increased morbidity, and lack of phase III randomized trials comparing survival and quality-of-life outcomes between contemporary bladder-preservation protocols and radical cystectomy.
The two main types of radiation schedules used in bladder-sparing therapy are split course and continuous approaches. Split course chemoradiation approaches typically use induction radiotherapy to 40 Gy followed by cystoscopic evaluation and consolidative radiotherapy of 25 Gy to complete responders ( Table 2 ). Five-year overall survival for studies with this approach ranges from 49% to 62%. The continuous scheme includes radiation dose from 50 to 69 Gy, with 5-year overall survival of 39% to 74% ( Table 3 ). Bladder-preservation rate with split course versus continuous course schemes is 36% to 47% and 42% to 61%, respectively.
Related posts:
Multidisciplinary Care of the Patient with Head and Neck Cancer
Multidisciplinary Management of Esophageal Cancer
Multidisciplinary Management of Gastric Cancer
Multidisciplinary Management of Small Cell Lung Cancer
Multimodality Treatment of Pleural Mesothelioma
Advances in the Multimodality Management of High-risk Prostate Cancer
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
