|Year : 2021 | Volume
| Issue : 4 | Page : 734-736
At crossroads with CROSS: Implementing the CROSS protocol in a resource-limited setting
Senthil J Rajappa
Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
|Date of Submission||11-Nov-2021|
|Date of Decision||24-Nov-2021|
|Date of Acceptance||24-Nov-2021|
|Date of Web Publication||29-Dec-2021|
Senthil J Rajappa
Basavatarakam Indo American Cancer Hospital and RI, Banjara Hills, Hyderabad - 500 034, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rajappa SJ. At crossroads with CROSS: Implementing the CROSS protocol in a resource-limited setting. Cancer Res Stat Treat 2021;4:734-6
Cancers of the esophagus and gastroesophageal (GE) junction are lethal, with a very poor 5-year survival. In a review published over 4 decades ago, around 58% of patients were reported to have had surgery, 39% underwent resection, and a third of them died in the immediate postoperative period with a dismal survival of 4% at 5 years. Since then, we have seen steady improvements in survival outcomes owing to improvements in the surgical techniques, expertise and postoperative care, better patient selection, and the addition of radiotherapy (RT), chemotherapy, and more recently, immune checkpoint inhibitors to the therapeutic arsenal.
Landmark trials that led to major changes in practice include RTOG 85-01 and CROSS, which established concurrent chemoradiotherapy (CRT) and CRT followed by surgery, respectively, as standards of care for patients with localized esophageal cancer., Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy have better outcomes compared to those who do not. Based on the pivotal results of the CROSS protocol and meta-analysis, the optimal treatment for squamous cell carcinoma (SCC) of the middle and lower esophagus is neoadjuvant CRT followed by surgery. In the CROSS protocol, the median and 5-year overall survival (OS) for the intention-to-treat population were 49.4 months and 47%, respectively. The benefit of CRT was more pronounced among those with SCC. The pCR rate and median OS for SCC were 49% and 81 months, respectively, compared to 23% and 43 months, respectively, for adenocarcinoma. The best approach to the neoadjuvant treatment of adenocarcinoma of the esophagus and GE junction remains to be defined. The most recent Neo-AEGIS study that randomized patients with adenocarcinoma of the esophagus and GE junction to receive either CRT followed by surgery or perioperative chemotherapy showed similar 3-year OS of 56% in both groups. According to the National Comprehensive Cancer Network, CRT carries a category 1 recommendation for patients with locally advanced carcinoma of the esophagus and GE junction. Recently, 1 year of nivolumab was approved as adjuvant therapy for patients with carcinoma of the esophagus or GE junction who have residual disease in the resected specimen post neoadjuvant CRT. Again, the benefits of nivolumab were more for those with SCC than adenocarcinoma.
In this issue of Cancer Research, Statistics, and Treatment, Dora et al. have shared their experience of implementing the CROSS protocol at the Homi Bhabha Cancer Hospital in Sangrur, Punjab. Though the authors had adequate expertise to execute the CRT part of the protocol, patients had to be sent elsewhere (two other centers in Delhi) for their surgery. In their cohort of 55 patients who completed CRT, 32 patients (58.2%) underwent surgery (group A), while 23 (41.8%) did not (group B). Almost all patients (96% and 100% in groups A and B, respectively) had SCC. The majority of the patients had stage IIB or IIIA disease and positron emission tomography-computed tomography (CT) staging, and evaluation were performed for all patients by a multidisciplinary team before treatment initiation. pCR was achieved in 59% of patients. The median disease-free survivals (DFS) in Group A and Group B were 8 months (range, 0–38) and 14 months (range, 0–29), respectively, and the 2-year DFS were 57.8% and 73.3%, respectively. Median and 2-year OS in Group A and Group B were 17 months (range, 3–43) and 52.6%, and 17 months (range, 2–31), and 53.5%, respectively. None of these differences were statistically significant.
About 58% of patients completed trimodality therapy. Major reasons for foregoing surgery included feeling well (34.8%) and inoperability (34.8%) as assessed on the presurgery CT scan. This figure seems quite high compared to the CROSS protocol, where 168 of 171 patients (98.2%) underwent surgery post neoadjuvant CRT and 161 (94.2%) had resection, of which 92% were R0. The median number of RT days in group A was 40 (range, 30–44) compared to 35 days in group B (range, 30–126), with reasons for the delay being unclear. This delay is surprising, especially when there were no gade 3/4 toxicities reported. The pCR rate in those who underwent surgery was 59.4%, which is comparable to that in the CROSS trial (49%). Although a few of these patients who did not undergo surgery received RT boost, the effect of this delayed additional dose of RT on pCR and local control is unclear. The standard RT dose for patients who receive definitive CRT is 50.4 Gy, with lack of benefit for further dose escalation.,
Despite 100% of patients having an R0 resection and nearly 60% achieving pCR, the median OS for the resected group was a dismal 17 months. This is nowhere close to the 81 months for SCC reported in the CROSS study. The major reason for the poor OS in this series was the high operative mortality (6 [18.8%] of 32 patients). Moreover, 5 (15.6%) out of 32 died of unrelated causes. Shorter follow-up, as mentioned by the authors, is unlikely to be the cause for this poor survival. Surgical mortality for transthoracic esophagectomies in published Indian series is around 5%. About 70% of patients had video-assisted thoracoscopic surgery, and the median number of harvested nodes was around 12. Although the optimal lymph nodal yield post CRT to define the adequacy of surgery is unclear, the accepted number is 15. Minimal access esophagectomy and two-field lymph node dissection need high level of expertise and postoperative care. Though the surgeries were performed in large referral hospitals, the outcomes were far from desirable. Surgery remains the most important component of trimodality therapy. Inadequate surgery and poor-quality postoperative care result in suboptimal outcomes.
Although the authors have to be appreciated for trying their best to follow-up the patients telephonically, nearly 70% did not have any imaging investigations done beyond CRT. With no imaging/endoscopy and telephonic follow-up, the reported DFS in group B is likely to be over-estimated and erroneous. Follow-up was also better in the surgery arm. The median and 2-year OS for Groups A and B were similar (17 months and 53%). Given the small sample size and retrospective nature of the study, any comparisons between groups are best avoided and should be interpreted with caution. These comparisons should not lead to any conclusions regarding the superiority of one arm over the other.
What do these results teach us? Implementing the CROSS protocol in the real world comes with challenges. These include patients opting out of surgery, either due to feeling well, out of fear of surgery, and more importantly, lack of surgical expertise and necessary postoperative care, apart from many other social, financial, and logistic reasons. First and foremost, it is necessary to develop an expert multispecialty team comprising all the major players, including radiologists, pathologists, clinicians, and rehabilitation specialists. In case this is not possible, the treating team should ensure timely referral to a higher center where the necessary expertise is available.
Can definitive CRT be an alternative to trimodality treatment in centers where surgical expertise is not available? Ideally, not. If trimodality treatment is the optimal therapy, then every effort should be made to refer for surgery rather than offer a suboptimal alternative. There are no large-scale randomized trials comparing the two strategies. However, available evidence favors trimodality therapy over definitive CRT. Definitive CRT is preferred only for patients with SCC of the upper third of the esophagus. For tumors of the middle and the lower third of the esophagus, the decision to give definitive CRT as an alternative should ideally be made upfront rather than after neoadjuvant CRT. This is to ensure that adequate doses of RT are delivered without a break. Escalation of RT doses beyond 50.4 Gy do not result in improved outcomes compared to standard doses., Since some studies show that preoperative chemotherapy is associated with less surgical morbidity, could this be an alternative to neoadjuvant CRT? Pending the results of randomized trials trying to answer this question, trimodality therapy should be adopted wherever possible., While there has been a gradual shift toward perioperative chemotherapy for patients with adenocarcinoma, neoadjuvant CRT followed by surgery remains the treatment of choice for SCC of the middle and lower third of the esophagus including the GE junction.
We get one chance to treat and possibly cure our patients with localized esophageal cancer, and surgery remains the most important part of the trimodality approach. We need to help patients to CROSS the road to get high-quality surgery and the postoperative care that they deserve. Cancer gives us one chance, and we cannot afford to throw that away.
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Conflicts of interest
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