NEWS & VIEWS
‘‘
Being able to deliver immunotherapy by smart sequencing … will become an increasingly important strategic goal
’’
other immunotherapeutic approaches, such as cytokines that increase the number of activated T‑cells in the circulation, or conventional cancer therapies, such as targeted kinase inhibitors, chemotherapy or radiotherapy. Patients with BRAF-mutated advancedstage melanoma have the option of receiving treatment with ipilimumab or a BRAF inhibitor (such as vemurafenib or dabrafenib), and possibly in the near future a combination of a BRAF inhibitor and a MEK inhibitor (dabra fenib plus trametinib), will become the next standard of care, based on the efficacy of this combination to significantly prolong progression-free survival (PFS) compared with dabrafenib alone.7 Compared with a PFS of approximately 2 months with dacarbazine, and around 6 months with a BRAF inhibitor, a PFS of >9 months was observed with the combination of a BRAF inhibitor and MEK inhibitor.7 The distinct activity profiles of the two classes of agents, together with recent evidence that BRAF inhibition has immune-enhancing properties, suggest combination therapy might prove beneficial. A phase I study to investigate the combination of ipilimumab and vemura fenib, however, was associated with four to five times higher-than-expected rates of hepatotoxicity suggesting that concurrent treatment may not be possible.8 However, the timing of administration of the various agents in this dual approach (immunotherapy and cytotoxic agents of any nature, including tyrosine kinase inhibitors) will be of great interest. In this approach, the administration of agents that induce a quick transient response (such as seen with BRAF and MEK inhibitors) can create the time and space to administer immuno-oncologic agents. Being able to deliver immunotherapy by smart sequencing of different treatments will become an increasingly important strategic goal. Treatment with some chemotherapies can result in tumour cell stress and death that stimulate a tumour-specific immune response, or increase levels of tumour surface molecules that facilitate recognition by the immune system. Immunogenic cell deathinducing agents can thus be successfully combined with an immuno-oncologic agent, resulting in an enhanced anticancer immune response.9 Another interesting concept is the 182 | APRIL 2014 | VOLUME 11
possibility of inducing immune-mediated abscopal effects, as seen with radiotherapy. Here, significant tumour regression both at the site of irradiation and outside areas support the notion of an enhanced systemic immune response and suggest localized radiotherapy in combination with immuno‑oncology is worth pursuing.10 Durable tumour control and long-term survival depend on harnessing the power of the immune system. Data with agents that block CTLA‑4, PD1 and other checkpoint proteins are not only providing a benchmark against which future therapies will be compared, but are stimulating interest in alternative sequencing or smart combination approaches that could improve outcomes even further. In changing the treatment landscape, immuno-oncology advances currently offer renewed hope to patients with advanced melanoma and to patients with other solid tumours in the near future. Cancer Institute (A.M.M.E.), Department of Dermatology (C.R.), Gustave Roussy Cancer Campus, Grand Paris, 114 rue Édouard Vaillant, 94805 Villejuif, France. Correspondence to: A.M.M.E. [email protected] Acknowledgements The authors take full responsibility for the content of this publication, and confirm that it reflects their viewpoint and medical expertise. StemScientific, funded by Bristol-Myers Squibb, provided writing and editing support. Bristol-Myers Squibb did not influence the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.
Competing interests A.M.M.E. has participated in advisory boards for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, MSD; C.R. has participated in advisory boards for Amgen, Cellgene, Bristol-Myers Squibb, GlaxoSmithKline, MSD, Novartis, Roche. 1.
Robert, C., Soria, J. C. & Eggermont, A. M. Drug of the year: programmed death‑1 receptor/programmed death‑1 ligand‑1 receptor monoclonal antibodies. Eur. J. Cancer 49, 2968–2971 (2013). 2. Schadendorf, D. et al. Pooled analysis of longterm survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma [abstract]. Eur. J. Cancer 49, LBA24 (2013). 3. Topalian, S. L. et al. Safety, activity, and immune correlates of anti‑PD‑1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012). 4. Hamid, O. et al. Safety and tumour responses with lambrolizumab (anti‑PD‑1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013). 5. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013). 6. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012). 7. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012). 8. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365–1366 (2013). 9. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Ann. Rev. Immunol. 31, 51–72 (2013). 10. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
COLORECTAL CANCER
Adjuvant chemotherapy for rectal cancer—an unresolved issue Manisha Palta, Brian G. Czito and Christopher G. Willett
Several clinical trials have addressed the role of adjuvant chemotherapy following neoadjuvant chemoradiation and surgery for rectal cancer. The recently published EORTC 22921 study adds further debate to the merits of adjuvant chemotherapy in this setting. Palta, M. et al. Nat. Rev. Clin. Oncol. 11, 182–184 (2014); published online 18 March 2014; doi:10.1038/nrclinonc.2014.43
Substantial improvements have been made in the management of rectal cancer over the past 20 years; however, the use of adjuvant chemotherapy following neoadjuvant chemoradiotherapy is highly controversial. The long-term results of the EORTC 22921 study adds fuel to the flame of controversy over the merits of adjuvant chemotherapy
following preoperative chemoradiotherapy (CRT) and surgery in patients with clinical stage T3/T4 resectable rectal cancer. Following launch of this trial in 1993, 1,011 patients ≤80 years of age, with performance status 0–1 and tumours within 15 cm of the anal verge, were randomly assigned to treatment with preoperative radiotherapy, www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS preo perative CRT, preoperative radio therapy and adjuvant chemotherapy, or pre operative CRT and adjuvant chemotherapy.1 The chemot herapy regimen consisted of 5-fluorouracil (5-FU, 350 mg/m2/day) and leucovorin (20 mg/m 2/day) for 5 days, delivered in two courses with radiotherapy and four courses in the adjuvant setting. The primary end point of the study was overall survival. The initial results of this study showed a local control benefit with the addition of chemot herapy to radiotherapy, however, there was no significant effect of adjuvant chemotherapy on disease-free survival (DFS) or overall survival.1 Separation of the Kaplan–Meier curves for DFS and overall survival suggested that the benefit of adjuvant chemotherapy might become apparent with long-term follow up. The updated results of the EORTC 22921 study with a median 10-year follow up have now been published. 2 Although local relapse rates improved in the cohorts receiving either adjuvant or neoadjuvant chemotherapy, there was no difference in 10-year DFS or overall survival with adjuvant chemotherapy compared with observation. Similarly, the 10-year rate of distant metastases was nearly 30% in all study arms. In contrast to the data reported in an earlier publication, there was no interaction between tumour response to preoperative therapy and the effect of adjuvant chemotherapy on DFS or overall survival.2,3
‘‘
…these data are not compelling to advocate the routine use of adjuvant chemotherapy
’’
Although rectal and colon cancer outcomes data are often considered as a single entity, there are important differences in therapy and patterns of failure between these two malignancies that need to be considered. Colon cancer is usually managed surgically with adjuvant systemic therapy reserved for patients at risk of systemic metastases, whereas both local and distant recurrences are important failure patterns in rectal cancer. Prior to the availability of EORTC data, the rationale of adjuvant chemotherapy after neoadjuvant CRT and surgery was extrapolated from the results of the large randomized trials in colon cancer and the US postoperative rectal studies. The adjuvant trials in colon cancer showed a 30–35% reduction in recurrence with adjuvant 5‑FU and leucovorin.4 Subsequently,
the MOSAIC trial in patients with colon cancer demonstrated superiority of adding oxaliplatin to 5‑FU and leucovorin as adjuvant therapy (6-year overall survival 78.5% versus 76%, respectively).5 For rectal cancer, several trials carried out in the USA in the 1970s and 1980s established the efficacy of CRT and adjuvant 5‑FU-based chemo therapy after surgery. These trials demonstrated not only enhanced local control with the addition of concurrent chemotherapy, but also an improvement in overall survival and reduction in distant metastasis. These factors clearly advocate for specific rectal cancer trials to assess the efficacy of adjuvant chemotherapy in the setting of neoadjuvant CRT and surgery. The role of adjuvant chemotherapy in rectal malignancies has been recently investigated further. In an Italian randomized trial, patients with locally advanced rectal cancer receiving preoperative therapy and surgery were randomized to observation versus adjuvant chemotherapy.6 Distant metastasis developed in 24% of patients in both groups with no differences in 5-year or 10-year overall survival. These results are in agreement with data reported in the EORTC 22921 trial, although final publication is awaited.6 Furthermore, a multicentre randomized control trial from the Netherlands evaluated 470 patients with stage II or III rectal cancer assigned to observation or adjuvant chemotherapy. The adjuvant regimen included either 5‑FU in combination with leucovorin or capecitabine after preoperative radiotherapy or CRT followed by total mesorectal excision (TME). At a median follow up of 4 years there was no substantial difference in the 5‑year DFS (58% in the observation arm and 62% in adjuvant chemotherapy arm) or overall survival (~75% in both arms).7 Finally, a third study from the UK closed prematurely after accruing 113 of an intended 800 patients. In this study, patients were randomly assigned to observation versus capecitabine and oxaliplatin (XELOX) for six cycles following neoadjuvant CRT. However, similarly to the Italian and Dutch studies, this underpowered study did not demonstrate a difference in DFS or overall survival between the two arms of the trial.8 With the caveats of these trials, these data are not compelling to advocate the routine use of adjuvant chemotherapy. All the studies reported herein do not demonstrate a survival benefit for the adjuvant setting; however, the role of adjuvant chemotherapy is still a point of debate and there is little consensus among guideline
NATURE REVIEWS | CLINICAL ONCOLOGY
Thinkstock
committees in the USA as well as in other countries. The statistical power of the EORTC and other trials to discern a benefit for adjuvant chemotherapy has been questioned. These trials are limited by small patient numbers compared to trials of adjuvant therapy for colon cancer where accrual is in the thousands. Similarly, the relevance of the results reported in the postoperative rectal cancer trials to contemporary manage ment of this cancer is ambiguous. In addition, an important and common observation among all adjuvant chemotherapy trials is poor compliance with the protocol treatment, and this aspect might dilute the actual benefit of the treatment in question. In the EORTC trial less than 43% of the patients assigned to adjuvant chemotherapy received the planned dose within the planned interval and more than a quarter did not start adjuvant chemotherapy. As a consequence of the poor compliance rates with adjuvant chemotherapy, clinical trials are now starting to incorporate chemo therapy in the neoadjuvant setting. For example, the recently updated Grupo Cáncer de Recto 3 study compared neoadjuvant with adjuvant chemotherapy (both arms receiving neoadjuvant CRT). Compliance in the adjuvant chemot herapy arm was 57% whereas 94% of patients received the planned four cycles of neoadjuvant chemotherapy.9 The 5-year overall survival was 77.9% in the adjuvant chemotherapy arm and 74.7% in the neoadjuvant chemotherapy arm (P = 0.64).10 Furthermore, two ongoing trials, in the USA and Europe, are evaluating the effect of incorporating chemotherapy in the neoadjuvant setting. In the USA the ongoing PROSPECT trial (NCT01515787) is attempting to randomly assign 1,000 patients with rectal cancer to receive either standard VOLUME 11 | APRIL 2014 | 183
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…the EORTC 22921 study results challenge the accepted dogma of routinely using adjuvant chemotherapy…
1.
5‑FU or capecitabine-based CRT, versus six cycles of 5‑FU, leucovorin and oxaliplatin (FOLFOX) followed by response assessment with CRT reserved for poor responders (
‘‘
Being able to deliver immunotherapy by smart sequencing … will become an increasingly important strategic goal
’’
other immunotherapeutic approaches, such as cytokines that increase the number of activated T‑cells in the circulation, or conventional cancer therapies, such as targeted kinase inhibitors, chemotherapy or radiotherapy. Patients with BRAF-mutated advancedstage melanoma have the option of receiving treatment with ipilimumab or a BRAF inhibitor (such as vemurafenib or dabrafenib), and possibly in the near future a combination of a BRAF inhibitor and a MEK inhibitor (dabra fenib plus trametinib), will become the next standard of care, based on the efficacy of this combination to significantly prolong progression-free survival (PFS) compared with dabrafenib alone.7 Compared with a PFS of approximately 2 months with dacarbazine, and around 6 months with a BRAF inhibitor, a PFS of >9 months was observed with the combination of a BRAF inhibitor and MEK inhibitor.7 The distinct activity profiles of the two classes of agents, together with recent evidence that BRAF inhibition has immune-enhancing properties, suggest combination therapy might prove beneficial. A phase I study to investigate the combination of ipilimumab and vemura fenib, however, was associated with four to five times higher-than-expected rates of hepatotoxicity suggesting that concurrent treatment may not be possible.8 However, the timing of administration of the various agents in this dual approach (immunotherapy and cytotoxic agents of any nature, including tyrosine kinase inhibitors) will be of great interest. In this approach, the administration of agents that induce a quick transient response (such as seen with BRAF and MEK inhibitors) can create the time and space to administer immuno-oncologic agents. Being able to deliver immunotherapy by smart sequencing of different treatments will become an increasingly important strategic goal. Treatment with some chemotherapies can result in tumour cell stress and death that stimulate a tumour-specific immune response, or increase levels of tumour surface molecules that facilitate recognition by the immune system. Immunogenic cell deathinducing agents can thus be successfully combined with an immuno-oncologic agent, resulting in an enhanced anticancer immune response.9 Another interesting concept is the 182 | APRIL 2014 | VOLUME 11
possibility of inducing immune-mediated abscopal effects, as seen with radiotherapy. Here, significant tumour regression both at the site of irradiation and outside areas support the notion of an enhanced systemic immune response and suggest localized radiotherapy in combination with immuno‑oncology is worth pursuing.10 Durable tumour control and long-term survival depend on harnessing the power of the immune system. Data with agents that block CTLA‑4, PD1 and other checkpoint proteins are not only providing a benchmark against which future therapies will be compared, but are stimulating interest in alternative sequencing or smart combination approaches that could improve outcomes even further. In changing the treatment landscape, immuno-oncology advances currently offer renewed hope to patients with advanced melanoma and to patients with other solid tumours in the near future. Cancer Institute (A.M.M.E.), Department of Dermatology (C.R.), Gustave Roussy Cancer Campus, Grand Paris, 114 rue Édouard Vaillant, 94805 Villejuif, France. Correspondence to: A.M.M.E. [email protected] Acknowledgements The authors take full responsibility for the content of this publication, and confirm that it reflects their viewpoint and medical expertise. StemScientific, funded by Bristol-Myers Squibb, provided writing and editing support. Bristol-Myers Squibb did not influence the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.
Competing interests A.M.M.E. has participated in advisory boards for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, MSD; C.R. has participated in advisory boards for Amgen, Cellgene, Bristol-Myers Squibb, GlaxoSmithKline, MSD, Novartis, Roche. 1.
Robert, C., Soria, J. C. & Eggermont, A. M. Drug of the year: programmed death‑1 receptor/programmed death‑1 ligand‑1 receptor monoclonal antibodies. Eur. J. Cancer 49, 2968–2971 (2013). 2. Schadendorf, D. et al. Pooled analysis of longterm survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma [abstract]. Eur. J. Cancer 49, LBA24 (2013). 3. Topalian, S. L. et al. Safety, activity, and immune correlates of anti‑PD‑1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012). 4. Hamid, O. et al. Safety and tumour responses with lambrolizumab (anti‑PD‑1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013). 5. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013). 6. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012). 7. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012). 8. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365–1366 (2013). 9. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Ann. Rev. Immunol. 31, 51–72 (2013). 10. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
COLORECTAL CANCER
Adjuvant chemotherapy for rectal cancer—an unresolved issue Manisha Palta, Brian G. Czito and Christopher G. Willett
Several clinical trials have addressed the role of adjuvant chemotherapy following neoadjuvant chemoradiation and surgery for rectal cancer. The recently published EORTC 22921 study adds further debate to the merits of adjuvant chemotherapy in this setting. Palta, M. et al. Nat. Rev. Clin. Oncol. 11, 182–184 (2014); published online 18 March 2014; doi:10.1038/nrclinonc.2014.43
Substantial improvements have been made in the management of rectal cancer over the past 20 years; however, the use of adjuvant chemotherapy following neoadjuvant chemoradiotherapy is highly controversial. The long-term results of the EORTC 22921 study adds fuel to the flame of controversy over the merits of adjuvant chemotherapy
following preoperative chemoradiotherapy (CRT) and surgery in patients with clinical stage T3/T4 resectable rectal cancer. Following launch of this trial in 1993, 1,011 patients ≤80 years of age, with performance status 0–1 and tumours within 15 cm of the anal verge, were randomly assigned to treatment with preoperative radiotherapy, www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS preo perative CRT, preoperative radio therapy and adjuvant chemotherapy, or pre operative CRT and adjuvant chemotherapy.1 The chemot herapy regimen consisted of 5-fluorouracil (5-FU, 350 mg/m2/day) and leucovorin (20 mg/m 2/day) for 5 days, delivered in two courses with radiotherapy and four courses in the adjuvant setting. The primary end point of the study was overall survival. The initial results of this study showed a local control benefit with the addition of chemot herapy to radiotherapy, however, there was no significant effect of adjuvant chemotherapy on disease-free survival (DFS) or overall survival.1 Separation of the Kaplan–Meier curves for DFS and overall survival suggested that the benefit of adjuvant chemotherapy might become apparent with long-term follow up. The updated results of the EORTC 22921 study with a median 10-year follow up have now been published. 2 Although local relapse rates improved in the cohorts receiving either adjuvant or neoadjuvant chemotherapy, there was no difference in 10-year DFS or overall survival with adjuvant chemotherapy compared with observation. Similarly, the 10-year rate of distant metastases was nearly 30% in all study arms. In contrast to the data reported in an earlier publication, there was no interaction between tumour response to preoperative therapy and the effect of adjuvant chemotherapy on DFS or overall survival.2,3
‘‘
…these data are not compelling to advocate the routine use of adjuvant chemotherapy
’’
Although rectal and colon cancer outcomes data are often considered as a single entity, there are important differences in therapy and patterns of failure between these two malignancies that need to be considered. Colon cancer is usually managed surgically with adjuvant systemic therapy reserved for patients at risk of systemic metastases, whereas both local and distant recurrences are important failure patterns in rectal cancer. Prior to the availability of EORTC data, the rationale of adjuvant chemotherapy after neoadjuvant CRT and surgery was extrapolated from the results of the large randomized trials in colon cancer and the US postoperative rectal studies. The adjuvant trials in colon cancer showed a 30–35% reduction in recurrence with adjuvant 5‑FU and leucovorin.4 Subsequently,
the MOSAIC trial in patients with colon cancer demonstrated superiority of adding oxaliplatin to 5‑FU and leucovorin as adjuvant therapy (6-year overall survival 78.5% versus 76%, respectively).5 For rectal cancer, several trials carried out in the USA in the 1970s and 1980s established the efficacy of CRT and adjuvant 5‑FU-based chemo therapy after surgery. These trials demonstrated not only enhanced local control with the addition of concurrent chemotherapy, but also an improvement in overall survival and reduction in distant metastasis. These factors clearly advocate for specific rectal cancer trials to assess the efficacy of adjuvant chemotherapy in the setting of neoadjuvant CRT and surgery. The role of adjuvant chemotherapy in rectal malignancies has been recently investigated further. In an Italian randomized trial, patients with locally advanced rectal cancer receiving preoperative therapy and surgery were randomized to observation versus adjuvant chemotherapy.6 Distant metastasis developed in 24% of patients in both groups with no differences in 5-year or 10-year overall survival. These results are in agreement with data reported in the EORTC 22921 trial, although final publication is awaited.6 Furthermore, a multicentre randomized control trial from the Netherlands evaluated 470 patients with stage II or III rectal cancer assigned to observation or adjuvant chemotherapy. The adjuvant regimen included either 5‑FU in combination with leucovorin or capecitabine after preoperative radiotherapy or CRT followed by total mesorectal excision (TME). At a median follow up of 4 years there was no substantial difference in the 5‑year DFS (58% in the observation arm and 62% in adjuvant chemotherapy arm) or overall survival (~75% in both arms).7 Finally, a third study from the UK closed prematurely after accruing 113 of an intended 800 patients. In this study, patients were randomly assigned to observation versus capecitabine and oxaliplatin (XELOX) for six cycles following neoadjuvant CRT. However, similarly to the Italian and Dutch studies, this underpowered study did not demonstrate a difference in DFS or overall survival between the two arms of the trial.8 With the caveats of these trials, these data are not compelling to advocate the routine use of adjuvant chemotherapy. All the studies reported herein do not demonstrate a survival benefit for the adjuvant setting; however, the role of adjuvant chemotherapy is still a point of debate and there is little consensus among guideline
NATURE REVIEWS | CLINICAL ONCOLOGY
Thinkstock
committees in the USA as well as in other countries. The statistical power of the EORTC and other trials to discern a benefit for adjuvant chemotherapy has been questioned. These trials are limited by small patient numbers compared to trials of adjuvant therapy for colon cancer where accrual is in the thousands. Similarly, the relevance of the results reported in the postoperative rectal cancer trials to contemporary manage ment of this cancer is ambiguous. In addition, an important and common observation among all adjuvant chemotherapy trials is poor compliance with the protocol treatment, and this aspect might dilute the actual benefit of the treatment in question. In the EORTC trial less than 43% of the patients assigned to adjuvant chemotherapy received the planned dose within the planned interval and more than a quarter did not start adjuvant chemotherapy. As a consequence of the poor compliance rates with adjuvant chemotherapy, clinical trials are now starting to incorporate chemo therapy in the neoadjuvant setting. For example, the recently updated Grupo Cáncer de Recto 3 study compared neoadjuvant with adjuvant chemotherapy (both arms receiving neoadjuvant CRT). Compliance in the adjuvant chemot herapy arm was 57% whereas 94% of patients received the planned four cycles of neoadjuvant chemotherapy.9 The 5-year overall survival was 77.9% in the adjuvant chemotherapy arm and 74.7% in the neoadjuvant chemotherapy arm (P = 0.64).10 Furthermore, two ongoing trials, in the USA and Europe, are evaluating the effect of incorporating chemotherapy in the neoadjuvant setting. In the USA the ongoing PROSPECT trial (NCT01515787) is attempting to randomly assign 1,000 patients with rectal cancer to receive either standard VOLUME 11 | APRIL 2014 | 183
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…the EORTC 22921 study results challenge the accepted dogma of routinely using adjuvant chemotherapy…
1.
5‑FU or capecitabine-based CRT, versus six cycles of 5‑FU, leucovorin and oxaliplatin (FOLFOX) followed by response assessment with CRT reserved for poor responders (
