Locally Advanced Pancreatic Cancer

Despite advances in immunotherapy, targeted therapies, and gene sequencing, initial chemotherapy for unresectable disease is still either gemcitabine-based combination therapy or FOLFIRINOX. Across numerous studies, patients with unresectable LAPC receiving FOLFIRINOX have a median progression-free survival of 3 to 20 months and a median overall survival of 10 to 32.7 months.¹⁰⁶ As with borderline resectable patients, FOLFIRINOX (Table 4) is generally reserved for unresectable patients with good functional status (ECOG 0–1 or Karnofsky Performance Status 90–100) and those at low risk for developing grade 3 or 4 systemic toxicities.¹⁰³ For these reasons it has generally not been frequently combined with other chemotherapeutic agents. However, FOLFIRINOX has been combined with radiation therapy in the consolidative neoadjuvant setting after induction chemotherapy. There have also been studies where traditional FOLFIRONIX was modified to improve tolerability, as evidenced by Gunturu et al’s study, which dose-reduced both fluorouracil and irinotecan by 25%, without compromising efficacy and simultaneously increasing tolerability.¹⁰⁷ Additionally, FOLFIRINOX requires infusional administration of the fluorouracil component, which may not be practical in certain patients. In that subset, capecitabine can be substituted. Among radiosensitizers during neoadjuvant therapy for unresectable LAPC, capecitabine has been shown to be as efficacious and less toxic than even gemcitabine.¹⁰⁸

As in borderline resectable disease, gemcitabine-based combination therapy is a standard treatment option in patients with unresectable disease (Table 5). In the phase 3 clinical trial by Van Hoff et al, the addition of nab-paclitaxel to gemcitabine versus gemcitabine alone led to significant improvements in overall and progression-free survival in metastatic patients. The objective response occurred at the expense of increased toxicity with peripheral neuropathy and myelosuppression, but the treatment was overall well tolerated.¹⁰⁹ This data led to the use of gemcitabine combined with nab-paclitaxel in patients with unresectable LAPC. Despite the improvements in objective response rates (ORR) with gemcitabine plus nab-paclitaxel, gemcitabine alone still has a role in LAPC (ORR of 23% with gemcitabine plus nab-paclitaxel versus 39% with FOLFIRINOX versus 10% with gemcitabine alone).¹⁰⁰ In elderly patients with poor functional status, significant comorbidities, or increased risk for developing toxicities, single-agent gemcitabine may be better tolerated than gemcitabine plus nab-paclitaxel or FOLFIRINOX with or without radiation therapy in LAPC. However, numerous clinical trials support the use of combination chemotherapy with FOLFIRINOX or gemcitabine plus nab-paclitaxel as reasonable options in LAPC patients with good functional status and adequate pain control and nutritional intake.¹⁰³

No head-to-head studies investigating FOLFIRINOX versus nab-paclitaxel and gemcitabine in patients with locally advanced disease have been published, but clinical trials are under way. Other combination therapies have been looked at through small retrospective or prospective studies, but no robust, large-scale clinical trials have been completed. For this reason, NCCN guidelines recommend enrollment of patients with LAPC into active clinical trials.

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• What is the role of radiation therapy in unresectable LAPC?

Despite the reported advantages of neoadjuvant radiation in patients with potentially resectable disease, there is significant debate regarding the timing and role of neoadjuvant radiation in patients with unresectable disease. Numerous comprehensive analyses and studiest indicate that chemoradiotherapy leads to significantly better overall survival compared to no therapy or radiation therapy alone in LAPC.^68,110,111 However, conflicting data support the use of upfront chemoradiotherapy in unresectable LAPC when compared to chemotherapy alone. Unfortunately, most prospective studies investigating the role of radiotherapy were performed following administration of single-agent gemcitabine, which is no longer considered standard of care for patients with LAPC. In spite of this, ECOG 4201 identified a statistically significant improvement in median overall survival following the addition of gemcitabine-based radiotherapy. Huguet et al in his review pointed out that upfront chemoradiotherapy was not superior to chemotherapy only and was associated with increased treatment toxicity.¹⁰⁵ Additionally, a recent phase 3 study looking at chemoradiotherapy versus chemotherapy alone in patients treated with gemcitabine found no difference in overall survival.¹¹² This can potentially be attributed to the fact that about 30% of patients with LAPC develop metastatic disease in the early phases of treatment due to poor control of local and systemically occult disease.¹¹³ Given the propensity for high rates of occult metastatic disease in LAPC, treatment paradigms and consensus guidelines recommend multi-agent systemic chemotherapy followed by chemoradiotherapy in select patients.

Based on current studies and until further clinical investigations are completed, consensus opinion indicates that the most appropriate approach in unresectable LAPC is to begin with induction chemotherapy (with either gemcitabine plus nab-paclitaxel, FOLFIRINOX, capecitabine, or other treatment combinations), followed by chemoradiation in the absence of disease progression when the first repeat imaging evaluation is completed (Figure). One important caveat regarding reimaging with CT in the neoadjuvant setting is that radiologic response may not correlate with pathologic response.¹¹⁴ PET-CT may have a role in predicting response to neoadjuvant therapy. Overall, induction chemotherapy followed by consolidative chemoradiation may confer numerous benefits: it removes the unnecessary burden and toxicity associated with radiotherapy in the nearly one third of patients who have pervasive disease progression during initial treatment; it allows testing and increases the chances of tolerating full-dose systemic chemotherapy; and it raises the likelihood of converting patients who do not progress to metastasis during the initial phase of treatment from unresectable to resectable status.^103,115 Despite the lack of strong conclusive data, the general agreement is that neoadjuvant chemoradiotherapy converts about one third of borderline and unresectable LAPC to an R0 resection.^95,103 There are very specific rationales for the addition of radiotherapy in LAPC, and these functions need to be better defined through further clinical trials.