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Intensive multidisciplinary treatment strategies and patient resilience to challenge long-term survival in metastatic colorectal cancer: a case report in real life and clinical practice

In fit metastatic colorectal cancer (MCRC), multidisciplinary treatment strategy integrating intensive FIr-B/FOx triplet chemotherapy associated to bevacizumab and secondary metastasectomies significantly improved clinical outcomes up to progression-free survival (PFS) 17 months and overall survival (OS) 44 months. A non-elderly woman affected by rectal cancer, lymph nodes involvement, synchronous unresectable liver metastases, was treated with first-line FIr-B/FOx integrated with two-stage liver resections, short course radiotherapy, anterior rectal resection, with a PFS 9 months and progression-free interval (PFI) 4 months off-treatment. After progression characterized by single liver and lymph node inferior mesenteric axis metastases, FIr-B/FOx was re-introduced, liver and lymph node resections were performed, with a PFS 8 months and PFI 3 months. FIr-B/FOx was further proposed due to bilateral lung, and liver metastases with stable disease, PFS 8 months. Patient experienced a limiting toxicity syndrome multiple sites (LTS-ms) with G3 diarrhea, G2 asthenia, nausea, requiring irinotecan reduction and 5-fluorouracil discontinuation, and subsequent oxaliplatin discontinuation, due to infusional hypersensitivity reaction. Overall, integrated first-line medical and surgical treatment strategies gained PFS 26 months. Further lines II–V of treatment obtained a combined PFS 28 months: modulated aflibercept/irinotecan, PFS 8 months; panitumumab, PFS 8 months, proposed due to KRAS/NRAS/BRAF wild-type and EGFR c.2156 G>C (p.G719A) mutation, achieving biomarkers reduction, lung, liver, lymph nodes partial responses; regorafenib, PFS 8 months; trifluridine-tipiracil, PFS 4 months and induced an LTS-ms, with febrile G4 leucopenia, G3 neutropenia, thrombocytopenia, asthenia, G2 anemia, diarrhea, hypotension. After 2 months of palliative care, patient died, at OS 58 months, gained by intensive medical/surgical treatments coupled with patient’s resilience. To date, selection of tailored medical treatments, according to clinical (age, performance and comorbidity status) and molecular (RAS/BRAF and pharmacogenomic analyses) evaluations, careful monitoring of individual toxicity syndromes, potential integration of metastasectomies, and furthermore individual resilience as patient life priority need to challenge MCRC long-term survival.


Introduction
Effectiveness of first-line medical and surgical treatment strategy of metastatic colorectal cancer (MCRC) is based on activity and efficacy of intensive treatments integrated with secondary resection of metastases, specifically liver metastases, increasing progression-free survival (PFS) up to 17 months (1)(2)(3)(4)(5)(6). Decision-making including functional, nutritional, co-morbidity status (Comorbidity Index Rating Scale, CIRS stage) selects patients fit for integrated strategies, or unfit, requiring tailored treatments (7), properly weighing expected safety and efficacy, also according to patient's life priorities.
In clinical practice, careful, continuous monitoring of patient's safety is required to realize integrated multidisciplinary intensive strategies in fit patients. To this aim, we developed the evaluation of limiting toxicity syndromes (LTS) to monitor individual patient toxicity (2,(13)(14)(15).
We reported a multidisciplinary management in clinical practice of fit, non-elderly, MCRC patient with synchronous, unresectable liver metastases treated with first-line FIr-B/FOx, converted to two-stage hepatectomy and rectal anterior resection, and further lines of treatment, driven by clinical, genetic and pharmacogenomic analyses, who approximately reached 5-year survival, to underline the relevance of multidisciplinary clinical management weighed with individual patient's resilience as life priority to challenge MCRC long-term survival.
We present the following article in accordance with the CARE reporting checklist (available at http://dx.doi. org/10.21037/atm-20-6636).

Case presentation
Due to right lumbar/abdominal pain, a 59-year-old woman, medical radiologist, with Lynch-like family history (a familial colon, two gastric, a bladder, a testicular cancer), made by herself an ultrasound showing multiple bilateral liver nodules, confirmed at computed tomography (CT) scan, the largest 10-cm diameter, and pathologic rectal enlargement with involved regional lymph nodes. Endoscopic examination confirmed rectal adenocarcinoma, 10  infusion fluorouracil 900 mg/m 2 /d d1-2, 8-9, 15-16, 22-23, every 28 days, for 3 cycles. Received dose-intensity (rDI) was >90% for each drug. Safety profile was characterized by: G2 diarrhea, G1 constipation, nausea, mucositis, asthenia, rhinitis, epistaxis, neuropathy, fever, alopecia. Partial response (PR) of liver metastases was obtained, and of primary rectal cancer, at CT scan, magnetic resonance imaging (MRI), endoscopic evaluation. Multidisciplinary team shared indication to fourth cycle, followed by twostage hepatectomy, short course radiotherapy (RT) and anterior rectal resection with protection ileum stoma. Five weeks after last chemotherapy administration, patient underwent multiple resections at left lobe, and 10 days after, right hepatectomy. Histological examination confirmed multiple metastatic lesions with consistent necrosis (35% to >60%), 2 out of 6 metastatic lymph nodes of hepatic artery. Six weeks after, patient underwent short-course RT 5 Gy for 5 days, and 9 weeks after hepatectomy, laparoscopic anterior rectal resection was performed. Histological examination confirmed rectal adenocarcinoma, TRG4 according to Mandard staging, ypT3 ypN2a; 5 out 19 metastatic lymph nodes with capsular invasion. KRAS/NRAS/BRAF wildtype genotype on rectal cancer cells was reported by next generation sequencing (NGS). Patient completed firstline medical treatment, two-stage liver metastasectomies, short-course RT, anterior rectal resection in 8 months; at PFS 9 months, progression-free interval (PFI) 4 months off-chemotherapy (Table 1), CT scan showed a new third segment liver metastasis (3 cm × 2.5 cm), and lymph node of inferior mesenteric axis involvement.
Due to KRAS/NRAS/BRAF wild-type genotype by NGS, associated with EGFR c.2156 G>C mutation (p.G719A), third line anti-EGFR panitumumab was proposed, 4 cycles. Consistent biomarkers reduction, >30% bilateral lung PR with excavation signs, liver metastases, thoracicabdominal lymph nodes was obtained. Further 4 cycles were administered. At PFS 8 months, CT scan showed increase of thoracic lymph nodes, right shoulder blade metastasis with discontinuation of cortex. During panitumumab, moderately differentiated, ulcerative, infiltrating, cutaneous squamous cell carcinoma of wing of nose was radically resected. Patient underwent RT 800 cGy, cryoablation of bone lesion 13 weeks apart.
No druggable, nor actionable molecular target was detected; ERBB2 and MGMT on liver metastases, MLH1, MSH2, MSH6, PMS2 in primary rectal cancer by immunohistochemistry were normally expressed; microsatellite instability analysis showed stable (MSI-S) genotype.
Then, patient was on best supportive care (BSC); 6 weeks after progression, she was admitted in Palliative Care Unit due to rapidly decreasing clinical conditions and 2 weeks apart she died. De novo metastatic disease OS was 58 months, gained by intensive integration between firstline FIr-B/FOx and secondary resections of liver metastases, short-course RT, primary rectal cancer resection, further second-fifth lines of treatment ( Table 1).
All procedures performed in this case report were in accordance with the ethical standards of the institutional research committee and with the Helsinki Declaration (as revised in 2013).
Step-by-step, patient was informed about diagnostic, clinical, biologic features, each proposed multidisciplinary treatment strategy. She shared each proposed treatment, signed written informed consent. Written informed consent was obtained for publication of any potentially identifiable images or data included in this article.

Discussion
The complexity of combined clinical and human features frequently and variably characterizing MCRC patients are summarized in the reported CRC patient who gained OS 58 months, due to the efficacy of subsequent multidisciplinary intensive medical and surgical treatment strategies and, more, due to her resilience to challenge the affecting metastatic disease, as a life priority. Patient was affected by bulky, bilateral liver-limited metastases from locally advanced rectal cancer with lymph nodes metastases. She was fit for multidisciplinary intensive first-line FIr-B/ FOx (2), previously developed from doublet and triplet chemotherapy (16,17), and after a PR, liver metastases were converted to resectability (4), and also resection of primary cancer after short-course RT was performed. Eight months of intensive, integrated medical, surgical, radio-therapeutic approaches converted the bulky into oligometastatic disease, consisting of single liver and inferior mesenteric nodal metastasis, at PFS 9 months. Two further FIr-B/FOx cycles re-introduction were proposed due to PFI 4 and 3 months, respectively, obtained by integrated metastasectomies, gaining overall PFS 26 months and OS 58 months (8).
In the reported patient, further lines of treatment raised OS 31 months from second line treatment: second line modified schedule/dose aflibercept/irinotecan gaining PR of liver metastases, integrated with stereotactic radiation therapy, PFS 8 months; third line anti-EGFR panitumumab, driven by KRAS/NRAS/BRAF wild-type and EGFR c.2156 G>C mutation (p.G719A), PR of bilateral lung, liver, lymph nodes metastases, PFS 8 months; fourth line regorafenib achieved a stable disease, PFS 8 months; fifth line trifluridine-tipiracil, PFS 4 months before markedly disease progression. In patients resistant or progressing after oxaliplatin-based first-line treatment, aflibercept/ FOLFIRI significantly improved OS 13.5 months, PFS 6.9 months, ORR 19.8%, and 22.3% of patients reached 30 months OS; in real life, PFS 5.3-6.8 months, OS 12 months, ORR 21.8% were reported; modified schedules/ doses required in >50% of patients did not significantly affect clinical outcomes. Synchronous MCRC patients showed significantly worse PFS 5 months, OS 10 months, while left-sided longer PFS 7 months, OS 12 months. Prevalently reported limiting toxicities were diarrhea, asthenia, mucositis, neutropenia, hypertension (9).
In KRAS/NRAS wild-type, second-line panitumumab/ FOLFIRI reached PFS 6.4 months. In early trial, panitumumab demonstrated efficacy after first and second lines failed (10). Concomitant EGFR mutation, reported in 1.6% colorectal cancer, even more justified third-line panitumumab treatment, achieving PFS 8 months; EGFR exon 18 c.2156 G>C (p.G719A) is a deleterious, gain-offunction mutation with predictive relevance. Other EGFR extracellular domain mutations detected after treatment justify acquired resistance to anti-EGFR.
Overall, reported patient affected by de novo, bulky metastatic disease gained OS 58 months, PFS 26 months of integrated first line, OS 31 months from second line, by intensive, multidisciplinary treatment strategies, requiring careful, continuous toxicity monitoring, patient's resilience for such a long commitment to complex, continuous therapeutic pathway, including several treatments lines, surgical resections, topical treatments. Careful evaluation of toxicity syndromes represents a clinical parameter measuring how much patient suffers from oncological treatments, indicating individual resilience.
Step-by-step, patient was informed about diagnostic, clinical, biologic features of disease and multidisciplinary strategy. Clinical management was shared with patient, weighing each proposed treatment with patient's priorities, regarding options, safety, implications on daily living, modulations/ suspensions, surgery and integration of interventional approaches. In individual MCRC patient fit for intensive treatments, clinical outcome and care also depends upon resilience, careful monitored at each step of disease evolution.

Conclusions
In clinical practice, selection of MCRC patients eligible for intensive medical treatments to achieve optimal activity and long-term OS by close integration with surgical strategies should evaluate biological (RAS/BRAF), clinical (age, performance status, CIRS) parameters, integrated with careful monitoring of individual safety using LTS, and patient's resilience as life priority to challenge long-term survival.