**2. Scientific-Technological Analysis**

In Scopus, the total of cancer-related papers in 2018 was 2,857,590 (see Figure 1a), and CRC-related papers numbered 167,366 (see Figure 1b); both subjects presented an exponential rise from 1970. The first documents indexed in Scopus related to CRC were report cases of medical interventions; for instance, Mr. Luke (1860) reported the surgery of an intestinal obstruction resulting from CRC [9]. Similarly, Dunphy (1947) reported four cases of CRC and included a gross pathological evaluation of the tumors [10].

**Figure 1.** Number of publications of cancer in Scopus; (**a**) total number of cancer-related publications from 1860 to 2018 using the search string "TITLE-ABS-KEY (cancer)"; (**b**) total number of colorectal cancer-related publications from 1947 to 2018 using the search string "TITLE-ABS-KEY (colorectal and cancer)".

In 1970, the first paper that reported the use of adjuvants was published by Adams et al. (1970), in which they compared the use of intralymphatic 5-fluorouracil (5-FU) and radioactive gold as adjuvants to surgical operations for colorectal carcinoma [11]. The next year, another two papers were

published, and today, more than 550 papers have been published on this matter per year (Scopus, search string "TITLE-ABS-KEY (colorectal and cancer and adjuvants)"), representing more than 7% (about 11,700 research papers) of the overall CRC research.

Patents related to cancer represented around 2,356,397 entries from 1898 to 2018. The number of patents related to CRC is about 306,240. The pattern of the number of patents per year is presented in Figure 2. It was interesting to find that that the number of patents related to cancer is lower than the number of scientific papers; this behavior can be related to the number of documents of clinical study cases that count for the papers.

**Figure 2.** Number of patents per year in (**a**) cancer and colorectal cancer (CRC) (data found in AcclaimIP)—the words "cancer" and "colorectal cancer" were examined in the title, abstract and claims, separately; (**b**) cancer adjuvants and colorectal cancer adjuvants (data found in AcclaimIP)—the words "cancer adjuvant" and "colorectal cancer adjuvant" were searched for in the title, abstract and claims, separately.

Regarding adjuvant therapies, it was found that adjuvants represent 20.0% of the overall cancer patents, and for CRC, adjuvants represent 39.3%. Thus, the number of patents related to adjuvants is proportionally higher for CRC (approximately two-fold) than for overall cancers, which can be explained by the motivation of scientists to cure the most deadly cancer type.

By comparing Figures 1 and 2, it can be seen that adjuvants are more likely to be patented than to be scientifically published (12.6 K vs. 478.9 K) because scientists and companies prefer to protect their intellectual property that can be economically exploited. For instance, the global adjuvant market size was valued at USD 308.99 million in 2016 and is anticipated to grow with a compound annual growth rate (CAGR) of 10.6% [12]. Furthermore, it can be observed that while scientific papers grew rapidly, the number of patents grew until 2010 and then dropped. This behavior can be attributed to the recent difficulty of patenting because applicants' claims should be new and clearly different to previous work [13], which is vast in cancer research, meaning that only 50% of patent applications are adjudicated. This is also discouraging new applications, since authors and companies do not see an attractive cost–benefit ratio for the patenting process [13].

By analyzing the keywords in the latest 2000 papers in Scopus and the title phrases in 1000 patents in the Derwent software (Clarivate Analytics, PA, USA) and then grouping the main subjects (see Figure 3), it was found that adjuvants are the second group for cancer and CRC, with 28.5% and 23.0% of entries, respectively, showing the importance of adjuvant therapy for improving the success of cancer treatments. Emerging strategies such as immunotherapy and biomarkers for treating and classifying cancer were also found.

Regarding the group of adjuvants, it was found that the terms "drug" and "chemotherapy" are more important for CRC than for cancer overall (see Table 1), again exposing the importance of drug delivery strategies for CRC. The drugs with more studies in recent papers (organized per decreasing number of entries) for CRC treatment are 5-fluoraucil, bevacizumab, capecitabine, metformin, aspirin, and irinotecan. Aspirin and metformin drew attention because they are drugs that are used for other purposes. For instance, aspirin and acetyl-salicylates, are used for treating fever, inflammation and pain [14]; however, Garcia et al. (2012) concluded that daily aspirin use at any dose was associated with a 21% lower risk of all-cancer death [15], and Chang et al. (2009) reported that aspirin reduces the risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models, especially in tumors that overexpress cyclooxygenase-2, whereas aspirin can reduce that expression [16].


**Table 1.** Comparison of keyword groups in scientific papers for cancer adjuvants and colorectal cancer adjuvants. Two thousand papers were extracted from Scopus and examined in their keywords and the documents up to 31/12/2018; the keywords were grouped using VantagePoint.

By analyzing the patents, it was found that the title phrases were more difficult to group and that the topics, in general, were more disperse (see Figure 3c,d); however, adjuvants and pharmaceutical compositions represent more than the 15% of the entries, coming in second place after cancer types, which includes the entries of all cancer names. Likewise, the drugs grouped in pharmaceutical composition for CRC are more diverse, but include indazoles derivatives, heteroaryl derivatives, heterocyclic compounds, quinoline compounds, and tumorigenic inhibitors, among others. These compounds are anticancer agents that have shown antiproliferative activity against cancer cells [17,18].

**Figure 3.** Keyword and title phrase groups in the latest papers and patents up to 31/12/2018; (**a**) grouped keywords of cancer adjuvants in scientific papers; (**b**) grouped keywords of colorectal cancer adjuvants in scientific papers; (**c**) grouped title phrases of cancer adjuvants in patents; (**d**) grouped title phrases of colorectal cancer adjuvants in patents. Authors' keywords were extracted from 2000 scientific papers in Scopus and analyzed using VantagePoint. Title patent phrases were extracted from 1000 patents of Derwent and analyzed using VantagePoint.
